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    Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial. Xu Jianming,Shen Jie,Gu Shanzhi,Zhang Yun,Wu Lihua,Wu Jian,Shao Guoliang,Zhang Yanqiao,Xu Li,Yin Tao,Liu Jingfeng,Ren Zhenggang,Xiong Jianping,Mao Xianhai,Zhang Ling,Yang Jiayin,Li Lequn,Chen Xiaoming,Wang Zhiming,Gu Kangsheng,Chen Xi,Pan Zhanyu,Ma Kuansheng,Zhou Xinmin,Yu Zujiang,Li Enxiao,Yin Guowen,Zhang Xiao,Wang Shuni,Wang Quanren Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS:This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1. RESULTS:Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3-46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4-31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4-7.4) and 5.5 months (95% CI, 3.7-5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5-83.5) and 68.2% (95% CI, 59.0-75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. CONCLUSIONS:Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.. 10.1158/1078-0432.CCR-20-2571
    Camrelizumab in combination with apatinib in second-line or above therapy for advanced primary liver cancer: cohort A report in a multicenter phase Ib/II trial. Mei Kuimin,Qin Shukui,Chen Zhendong,Liu Ying,Wang Linna,Zou Jianjun Journal for immunotherapy of cancer BACKGROUND:Emerging clinical data suggest that an immune checkpoint inhibitor in combination with an antiangiogenic agent is a reasonable strategy for multiple malignancies. We assessed the combination of camrelizumab with apatinib in pretreated advanced primary liver cancer (PLC, cohort A) from a multicohort phase Ib/II trial. METHODS:Patients with PLC after prior systemic treatment(s) were administered camrelizumab (3 mg/kg, once every 2 weeks) plus apatinib (125, 250, 375, or 500 mg; once per day) in a 3+3 dose-escalation stage and subsequent expansion stage. The primary endpoints were tolerability and safety of study treatment. RESULTS:From April 2017 to July 2019, 28 patients (21 with hepatocellular carcinoma and 7 with intrahepatic cholangiocarcinoma) received camrelizumab plus apatinib. Two dose-limiting toxicities (both grade 3 diarrhea) were reported in the 500 mg cohort. Therefore, the 375 mg cohort was expanded. Of the 19 patients in the 375 mg cohort, dose reduction to 250 mg occurred in 8 patients within 2 months after treatment initiation. Of the 28 patients with PLC, 26 had grade ≥3 treatment-related adverse events, with hypertension being the most common (9/28). One treatment-related death occurred. The objective response rate was 10.7% (95% CI 2.3% to 28.2%). Median progression-free survival and overall survival were 3.7 months (95% CI 2.0 to 5.8) and 13.2 months (95% CI 8.9 to not reached), respectively. CONCLUSION:The combination of camrelizumab with apatinib had a manageable toxicity and promising antitumor activity in patients with advanced PLC. Apatinib at a dose of 250 mg is recommended as a combination therapy for further studies of advanced PLC treatment. TRIAL REGISTRATION NUMBERS:NCT03092895. 10.1136/jitc-2020-002191
    Development and Validation of a Contrast-Enhanced CT-Based Radiomics Nomogram for Prediction of Therapeutic Efficacy of Anti-PD-1 Antibodies in Advanced HCC Patients. Yuan Guosheng,Song Yangda,Li Qi,Hu Xiaoyun,Zang Mengya,Dai Wencong,Cheng Xiao,Huang Wei,Yu Wenxuan,Chen Mian,Guo Yabing,Zhang Qifan,Chen Jinzhang Frontiers in immunology Background:There is no study accessible now assessing the prognostic aspect of radiomics for anti-PD-1 therapy for patients with HCC. Aim:The aim of this study was to develop and validate a radiomics nomogram by incorporating the pretreatment contrast-enhanced Computed tomography (CT) images and clinical risk factors to estimate the anti-PD-1 treatment efficacy in Hepatocellular Carcinoma (HCC) patients. Methods:A total of 58 patients with advanced HCC who were refractory to the standard first-line of therapy, and received PD-1 inhibitor treatment with Toripalimab, Camrelizumab, or Sintilimab from 1st January 2019 to 31 July 2020 were enrolled and divided into two sets randomly: training set (n = 40) and validation set (n = 18). Radiomics features were extracted from non-enhanced and contrast-enhanced CT scans and selected by using the least absolute shrinkage and selection operator (LASSO) method. Finally, a radiomics nomogram was developed based on by univariate and multivariate logistic regression analysis. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility. Results:Eight radiomics features from the whole tumor and peritumoral regions were selected and comprised of the Fusion Radiomics score. Together with two clinical factors (tumor embolus and ALBI grade), a radiomics nomogram was developed with an area under the curve (AUC) of 0.894 (95% CI, 0.797-0.991) and 0.883 (95% CI, 0.716-0.998) in the training and validation cohort, respectively. The calibration curve and decision curve analysis (DCA) confirmed that nomogram had good consistency and clinical usefulness. Conclusions:This study has developed and validated a radiomics nomogram by incorporating the pretreatment CECT images and clinical factors to predict the anti-PD-1 treatment efficacy in patients with advanced HCC. 10.3389/fimmu.2020.613946
    Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Qin Shukui,Ren Zhenggang,Meng Zhiqiang,Chen Zhendong,Chai Xiaoli,Xiong Jianping,Bai Yuxian,Yang Lin,Zhu Hong,Fang Weijia,Lin Xiaoyan,Chen Xiaoming,Li Enxiao,Wang Linna,Chen Chunxia,Zou Jianjun The Lancet. Oncology BACKGROUND:Blocking the interaction between PD-1 and its ligands is a promising treatment strategy for advanced hepatocellular carcinoma. This study aimed to assess the antitumour activity and safety of the anti-PD-1 inhibitor camrelizumab in pretreated patients with advanced hepatocellular carcinoma. METHODS:This is a multicentre, open-label, parallel-group, randomised, phase 2 trial done at 13 study sites in China. Eligible patients were aged 18 years and older with a histological or cytological diagnosis of advanced hepatocellular carcinoma, had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every 2 or 3 weeks, via a centralised interactive web-response system using block randomisation (block size of four). The primary endpoints were objective response (per blinded independent central review) and 6-month overall survival, in all randomly assigned patients who had at least one dose of study treatment. Safety was analysed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment is closed. FINDINGS:Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for eligibility, of whom 220 eligible patients were randomly assigned and among whom 217 received camrelizumab (109 patients were given treatment every 2 weeks and 108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7-15·5). Objective response was reported in 32 (14·7%; 95% CI 10·3-20·2) of 217 patients. The overall survival probability at 6 months was 74·4% (95% CI 68·0-79·7)]. Grade 3 or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the most common were increased aspartate aminotransferase (ten [5%]) and decreased neutrophil count (seven [3%]). Two deaths were judged by the investigators to be potentially treatment-related (one due to liver dysfunction and one due to multiple organ failure). INTERPRETATION:Camrelizumab showed antitumour activity in pretreated Chinese patients with advanced hepatocellular carcinoma, with manageable toxicities, and might represent a new treatment option for these patients. FUNDING:Jiangsu Hengrui Medicine. 10.1016/S1470-2045(20)30011-5
    Editorial: Biomarkers of Immune-Checkpoint-Inhibitor Immunotherapies in Hepatocellular Carcinomas. Guo Zhanjun,Li Heng-Hong,Shiao Yih-Horng Frontiers in oncology 10.3389/fonc.2022.860964
    Tumour-associated macrophages in hepatocellular carcinoma: Pressing the metabolic switch to prevent T cell responses. O'Rourke Joanne M,Patten Daniel A,Shetty Shishir Journal of hepatology 10.1016/j.jhep.2019.05.019
    PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma. Lu Li-Gong,Zhou Zhi-Ling,Wang Xu-Yan,Liu Bo-Yuan,Lu Jin-Ying,Liu Shuai,Zhang Guang-Bo,Zhan Mei-Xiao,Chen Yun Gut OBJECTIVE:Patients with increased PD-L1 host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1 host cells in hepatocellular carcinoma (HCC). DESIGN:A total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1 cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies. RESULTS:We demonstrate that PD-L1 host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRCD86 glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2 glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties. CONCLUSIONS:Selectively modulating the 'context' of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy. 10.1136/gutjnl-2021-326350
    Emerging Role of PD-1/PD-L1 Inhibitors in Chronic Liver Diseases. Singh Vishakha,Khurana Amit,Allawadhi Prince,Banothu Anil Kumar,Bharani Kala Kumar,Weiskirchen Ralf Frontiers in pharmacology Programmed cell death protein 1 (PD-1)/PD-ligand (L)1, the immune checkpoint inhibitors have emerged as a promising strategy for the treatment of various diseases including chronic liver diseases (CLDs) such as hepatitis, liver injury and hepatocellular carcinoma (HCC). The role of PD-1/PD-L1 has been widely inspected in the treatment of viral hepatitis and HCC. PD-1 is known to play a crucial role in inhibiting immunological responses and stimulates self-tolerance by regulating the T-cell activity. Further, it promotes apoptosis of antigen-specific T-cells while preventing apoptosis of T cells. PD-L1 is a -membrane protein which is recognized as a co-inhibitory factor of immunological responses. Both, PD-1 and PD-L1 function together to downregulate the proliferation of PD-1 positive cells, suppress the expression of cytokines and stimulate apoptosis. Owing to the importance of PD-1/PD-L1 signaling, this review aims to summarize the potential of PD-1/PD-L1 inhibitors in CLDs along with toxicities associated with them. We have enlisted some of the important roles of PD-1/PD-L1 in CLDs, the clinically approved products and the pipelines of drugs under clinical evaluation. 10.3389/fphar.2021.790963
    Dysregulation of immune checkpoint proteins in hepatocellular carcinoma: Impact on metabolic reprogramming. Current opinion in pharmacology Hepatocellular carcinoma (HCC) is an inflammation-induced malignant disease of the liver. Abundant expression of immune checkpoint proteins has been reported in HCCs, which contribute to immune cell dysfunction and HCC progression. Immune checkpoint inhibitors as monotherapy or combination therapy have been approved by Food and Drug Administration for advanced HCCs. However, the median survival has not significantly improved, suggesting the need for exploring additional mechanisms to increase efficacy. Metabolic reprogramming is one of the mechanisms by which checkpoint proteins promote tumor growth and immune cell dysfunction. This review provides an insight into the role of immune checkpoint proteins on metabolic reprogramming in tumor and immune cells. An in-depth understating of these could help in the development of more efficacious and long-term therapies for HCC. 10.1016/j.coph.2022.102232
    Clinical course of liver injury induced by immune checkpoint inhibitors in patients with advanced malignancies. Ito Takanori,Ishigami Masatoshi,Yamamoto Takafumi,Mizuno Kazuyuki,Yamamoto Kenta,Imai Norihiro,Ishizu Yoji,Honda Takashi,Kawashima Hiroki,Yasuda Satoshi,Toyoda Hidenori,Yokota Kenji,Hase Tetsunari,Nishio Naoki,Maeda Osamu,Kato Masashi,Hashimoto Naozumi,Hibi Hideharu,Kodera Yasuhiro,Sone Michihiko,Ando Yuichi,Akiyama Masashi,Shimoyama Yoshie,Fujishiro Mitsuhiro Hepatology international BACKGROUND:The clinical course of liver injury induced by immune checkpoint inhibitors (ICIs) varies among individuals, and there were few reports on the therapeutic effects of corticosteroids based on the patterns of liver injury. METHODS:We evaluated the characteristics and clinical course of immune-related liver injury in 1214 patients treated with ICIs for advanced malignancies except for hepatocellular carcinoma between August 2014 and May 2021. RESULTS:During the follow-up period (median, 252 days), 58 patients (4.8%) had an immune-related liver injury (≥ Grade 3). The liver-injury patterns were hepatocellular (n = 26, 44.8%), mixed (n = 11, 19.0%), or cholestatic (n = 21, 36.2%), and the median time to onset of liver injury was 39, 81, and 53 days, respectively; the hepatocellular pattern occurred earlier than the other types (p = 0.047). Corticosteroids were administered to 30 (51.7%) patients; while liver injury was improved in almost all patients with the hepatocellular pattern (n = 13/14, 92.9%), that failed to show improvement in over half of the patients with the non-hepatocellular patterns, and three patients with mixed patterns needed secondary immunosuppression with mycophenolate mofetil. Liver biopsies performed in 13 patients mainly showed lobular injury, endothelialitis, and spotty necrosis with infiltration of T cells positive for CD3 and CD8, but not CD4 or CD20. CONCLUSION:The incidence pattern and therapeutic response to corticosteroids in immune-related liver injury differ according to the injury type. Although corticosteroids were effective for the hepatocellular pattern, an additional strategy for refractory non-hepatocellular patterns is needed. 10.1007/s12072-021-10238-y
    Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial. Hong Jung Yong,Cho Hee Jin,Sa Jason K,Liu Xiaoqiao,Ha Sang Yun,Lee Taehyang,Kim Hajung,Kang Wonseok,Sinn Dong Hyun,Gwak Geum-Youn,Choi Moon Seok,Lee Joon Hyeok,Koh Kwang Cheol,Paik Seung Woon,Park Hee Chul,Kang Tae Wook,Rhim Hyunchul,Lee Su Jin,Cristescu Razvan,Lee Jeeyun,Paik Yong Han,Lim Ho Yeong Genome medicine BACKGROUND:A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy. METHODS:Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells. RESULTS:The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% ([6/60] 95% CI, 2.4-17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. CONCLUSIONS:Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment. TRIAL REGISTRATION:NCT#03163992 (first posted: May 23, 2017). 10.1186/s13073-021-00995-8
    Gut Dysbiosis and Fecal Calprotectin Predict Response to Immune Checkpoint Inhibitors in Patients With Hepatocellular Carcinoma. Hepatology communications The gut microbiota is a well-known prognostic factor and a modulator of treatment sensitivity in patients with cancers treated with immune checkpoint inhibitors. However, data on hepatocellular carcinoma (HCC) are lacking. This study aimed to evaluate the prognostic role of the gut microbiota and changes produced by immunotherapy on the intestinal environment in patients with cirrhosis and HCC. Eleven patients treated with Tremelimumab and/or Durvalumab were included in the analysis. All study participants underwent gut microbiota profiling, quantification of fecal calprotectin, serum levels of zonulin-1, lipopolysaccharide binding protein (LBP), and programmed death-ligand 1 (PD-L1) at baseline and at each treatment cycle until the third cycle, then every three cycles until treatment discontinuation or last visit. The 6 patients who achieved disease control (DC) showed lower pretreatment fecal calprotectin (median, 12.5; interquartile range [IQR], 5-29 vs. median, 116; IQR, 59-129 µg/g; P = 0.047) and PD-L1 serum levels (median, 0.08; IQR, 0.07-0.09 vs. median, 1.04; IQR, 0.17-1.95 ng/mL; P = 0.02) than nonresponders. The relative abundance of Akkermansia (log2 fold change [FC], 2.72; adjusted P [Padj] = 0.012) was increased, whereas that of Enterobacteriaceae (log2 FC, -2.34; Padj = 0.04) was reduced in the DC group. During treatment, fecal calprotectin showed a temporal evolution opposite to the Akkermansia to Enterobacteriaceae ratio and gut microbiota alpha diversity, but similar to zonulin-1 and LBP. Bifidobacterium had a stable behavior in patients with a long follow-up, while Akkermansia was more variable. Akkermansia and Bifidobacterium showed similar temporal patterns and causative relationships with Prevotella, Veillonella, Ruminococcus, Roseburia, Lachnospira, Faecalibacterium, and Clostridium. Conclusion: A favorable composition of the gut microbiota and low intestinal inflammation are associated with achieving DC. The intestinal environment changes dynamically during therapy. 10.1002/hep4.1905
    Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma. Journal of hepatology BACKGROUND & AIMS:While immune checkpoint blockade (ICB) has shown promise in patients with hepatocellular carcinoma (HCC), it is associated with modest response rates and immune-related adverse events (irAEs) are common. In this study, we aimed to decipher immune trajectories and mechanisms of response and/or irAEs in patients with HCC receiving anti-programmed cell death 1 (anti-PD-1) therapy. METHODS:Pre- and on-treatment peripheral blood samples (n = 60) obtained from 32 patients with HCC (Singapore cohort) were analysed by cytometry by time-of-flight and single-cell RNA sequencing, with flow cytometric validation in an independent Korean cohort (n = 29). Mechanistic validation was conducted by bulk RNA sequencing of 20 pre- and on-treatment tumour biopsies and using a murine HCC model treated with different immunotherapeutic combinations. RESULTS:Single-cell analyses identified CXCR3CD8 effector memory T (T) cells and CD11c antigen-presenting cells (APC) as associated with response (p = 0.0004 and 0.0255, respectively), progression-free survival (p = 0.00079 and 0.0015, respectively), and irAEs (p = 0.0034 and 0.0125, respectively) in anti-PD-1-treated patients with HCC. Type-1 conventional dendritic cells were identified as the specific APC associated with response, while 2 immunosuppressive CD14 myeloid clusters were linked to reduced irAEs. Further analyses of CXCR3CD8 T cells showed cell-cell interactions specific to response vs. irAEs, from which the anti-PD-1 and anti-TNFR2 combination was harnessed to uncouple these effects, resulting in enhanced response without increased irAEs in a murine HCC model. CONCLUSIONS:This study identifies early predictors of clinical response to anti-PD-1 ICB in patients with HCC and offers mechanistic insights into the immune trajectories of these immune subsets at the interface between response and toxicity. We also propose a new combination immunotherapy for HCC to enhance response without exacerbating irAEs. CLINICAL TRIAL NUMBER:NCT03695952. LAY SUMMARY:Response rates to immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) remain modest and adverse events are common. Herein, we identified early predictors of response and gained an in-depth understanding of the immunological mechanisms behind response and adverse events in patients with HCC treated with ICB. We also proposed a new combination immunotherapy for HCC that enhances response without exacerbating adverse events. 10.1016/j.jhep.2022.03.039
    Immunotherapy in older patients with hepatocellular carcinoma. Lyu Ning,Yi Jun-Zhe,Zhao Ming European journal of cancer (Oxford, England : 1990) Hepatocellular carcinoma (HCC) is one of the most common types of cancer globally and is currently the third leading cause of cancer-related deaths. Recently, immunotherapy using immune checkpoint inhibitors (ICIs) has been shown with encouraging anticancer activity and safety in clinical trials. To reverse the phenomenon of tumours evading immune response, ICIs can be used to stimulate the natural antitumour potential of cancer cells by blocking the relevant checkpoints to activate T cells. However, the components and functions of the immune system may undergo a series of changes with ageing, known as 'immunosenescence,' potentially affecting the antitumour effect and safety of immunotherapy. In the current phase III clinical trials of ICIs including nivolumab, pembrolizumab and atezolizumab, the proportion of patients with HCC older than 65 years in CheckMate 459, KEYNOTE-240 and IMbrave150 is 51%, 58% and 50%, respectively, which is less than 70%-73% of epidemiological investigation. Therefore, the elderly population recruited in clinical trials may not accurately represent the real-world elderly patients with HCC, which affects the extrapolation of the efficacy and safety profile obtained in clinical trials to the elderly population in the real world. This review provides the latest advances in ICIs immuno-treatment available for HCC and relevant information about their therapeutic effects and safety on elderly patients. We discuss the benefits of ICIs for older HCC patients, and relevant recommendations about conducting further clinical trials are proposed for more complete answers to this clinical issue. 10.1016/j.ejca.2021.11.024
    PD-1 expression in hepatocellular carcinoma predicts liver-directed therapy response and bridge-to-transplant survival. Cancer immunology, immunotherapy : CII BACKGROUND:Hepatocellular carcinoma (HCC) patients undergo liver-directed therapy (LDT) to control tumor burden while awaiting liver transplantation with response impacting waitlist survival. In this study, we investigate the link between absolute lymphocyte count (ALC) and PD-1 expression with response to LDT and bridge-to-transplant survival. METHODS:Treatment-naïve HCC patients (n = 86) undergoing LDT were enrolled at a single center from August 2016-March 2020. Response to LDT was determined using mRECIST. Blood samples were collected on the day of LDT and at follow-up. Cells were analyzed for phenotype by flow cytometry. Outcomes were liver transplantation or tumor progression. RESULTS:Incomplete response to initial LDT was associated with tumor progression precluding liver transplantation (OR: 7.6, 1.7 - 33.3, P < 0.001). Univariate analysis of baseline T cell phenotypes revealed ALC (OR: 0.44, 0.24-0.85, P = 0.009) as well as intermediate expression of PD-1 on CD4 (OR: 3.3, 1.03-10.3, P = 0.034) and CD8 T cells (OR: 3.0, 0.99-8.8 P = 0.043) associated with incomplete response to LDT. Elevations in PD-1 expression were associated with increased risk of bridge-to-transplant tumor progression (HR: 3.2, 1.2-9.4). In patients successfully bridged to liver transplantation, pre-treatment peripheral PD-1 profile was associated with advanced tumor staging (P < 0.005) with 2/4 of patients with elevations in PD-1 having T3-T4 TNM staging compared to 0 with low PD-1 expression. CONCLUSION:Low lymphocyte count or elevated expression of the PD-1 checkpoint inhibitor is associated with incomplete response to LDT and increased risk of bridge-to-transplant tumor progression. Patients with impaired T cell homeostasis may benefit from PD-1 immunotherapy to improve response to LDT and improve bridge-to-transplant outcomes. 10.1007/s00262-021-03087-z
    T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma. Journal of hepatology BACKGROUND & AIMS:Despite recent translation of immunotherapies into clinical practice, the immunobiology of hepatocellular carcinoma (HCC), in particular the role and clinical relevance of exhausted and liver-resident T cells remain unclear. We therefore dissected the landscape of exhausted and resident T cell responses in the peripheral blood and tumor microenvironment of patients with HCC. METHODS:Lymphocytes were isolated from the blood, tumor and tumor-surrounding liver tissue of patients with HCC (n = 40, n = 10 treated with anti-PD-1 therapy). Phenotype, function and response to anti-PD-1 were analyzed by mass and flow cytometry ex vivo and in vitro, tissue residence was further assessed by immunohistochemistry and imaging mass cytometry. Gene signatures were analyzed in silico. RESULTS:We identified significant enrichment of heterogeneous populations of exhausted CD8+ T cells (TEX) in the tumor microenvironment. Strong enrichment of severely exhausted CD8 T cells expressing multiple immune checkpoints in addition to PD-1 was linked to poor progression-free and overall survival. In contrast, PD-1 was also expressed on a subset of more functional and metabolically active CD103+ tissue-resident memory T cells (TRM) that expressed few additional immune checkpoints and were associated with better survival. TEX enrichment was independent of BCLC stage, alpha-fetoprotein levels or age as a variable for progression-free survival in our cohort. These findings were in line with in silico gene signature analysis of HCC tumor transcriptomes from The Cancer Genome Atlas. A higher baseline TRM/TEX ratio was associated with disease control in anti-PD-1-treated patients. CONCLUSION:Our data provide information on the role of peripheral and intratumoral TEX-TRM dynamics in determining outcomes in patients with HCC. The dynamics between exhausted and liver-resident T cells have implications for immune-based diagnostics, rational patient selection and monitoring during HCC immunotherapies. LAY SUMMARY:The role of the immune response in hepatocellular carcinoma (HCC) remains unclear. T cells can mediate protection against tumor cells but are frequently dysfunctional and exhausted in cancer. We found that patients with a predominance of exhausted CD8+ T cells (TEX) had poor survival compared to patients with a predominance of tissue-resident memory T cells (TRM). This correlated with the molecular profile, metabolic and functional status of these cell populations. The enrichment of TEX was independently associated with prognosis in addition to disease stage, age and tumor markers. A high TRM proportion was also associated with better outcomes following checkpoint therapy. Thus, these T-cell populations are novel biomarkers with relevance in HCC. 10.1016/j.jhep.2022.02.032
    PD-1 blockade improves the anti-tumor potency of exhausted CD3CD56 NKT-like cells in patients with primary hepatocellular carcinoma. Tao Longxiang,Wang Shanshan,Kang Guijie,Jiang Shanyue,Yin Wenwei,Zong Lu,Li Jing,Wang Xuefu Oncoimmunology CD3CD56 NKT-like cells play pivotal roles in the anti-tumor immune defense response. However, little is known regarding circulating NKT-like cells in patients with primary hepatocellular carcinoma (HCC). In the present study, we demonstrate that circulating NKT-like cells in HCC patients are functionally impaired and anti-PD-1 blockade improves their anti-tumor potency. Circulating NKT cells were mainly comprised of CD8+ T cells. The frequencies and absolute counts of circulating NKT-like cells were comparable between HCC patents compared to healthy donors. NKT-like cells in HCC patients were impaired in their production of TNF-α and IFN-γ as well as cytotoxicity. The level of activating receptor NKG2D was significantly decreased on NKT-like cells in HCC patients. In contrast, the expression of inhibitory receptors PD-1, Tim-3, and CTLA-4 were markedly increased on NKT-like cells in HCC patients. Meanwhile, the expression of PD-L1 was also upregulated on NKT-like cells in HCC patients. In detail, PD-1 NKT-like cells expressed lower levels of NKG2D, higher levels of Tim-3, and CTLA-4, and less IFN-γ when compared with PD-1 NKT-like cells. Importantly, PD-1 blocked with anti-PD-1 antibody effectively improved the effector function of NKT-like cells from HCC patients or healthy donors. Our findings unveil the functional characterization of NKT-like cells in HCC patients and provide the potential targets to improve their function, which might benefit the optimization of HCC immunotherapy. 10.1080/2162402X.2021.2002068
    Hypothyroidism is a predictive factor of superior antitumour efficacy of programmed death 1 inhibitors in hepatocellular carcinoma. Xu Lei,Leng Chao,Chen Lin,Dong Hanhua,Chen Yifa,Chen Xiaoping International journal of cancer Programmed death 1 (PD-1) inhibitors are widely used for treatment of hepatocellular carcinoma (HCC). Hypothyroidism is commonly associated with this therapy, although the mechanism underlying this complication and effects on patient prognosis remain unclear. We retrospectively analysed the data of patients with HCC who received anti-PD-1 therapy at Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology between January 2018 and May 2020. Based on thyroid function evaluation, patients were categorised into hypothyroidism group and nonhypothyroidism group. Follow-up was completed on February 28, 2021. The primary endpoint of our study was progression free survival (PFS). The study included 74 patients, and the disease control rate was higher in hypothyroidism group (62.7%, 27/43) than in nonhypothyroidism group (36.4%, 11/31) (P = .020). The PFS was longer in hypothyroidism group (7.44 months) than in nonhypothyroidism group (5.68 months) (P = .006). Additionally, the PFS of patients with hypothyroidism before immunotherapy (6.27 months) was also longer than that in nonhypothyroidism group (5.68 months), although the difference was statistically nonsignificant (P = .527). Cox regression analysis showed that the hazard ratios of hypothyroidism, Child-Pugh grade B at initial admission and serum gamma-glutamyl transferase levels >71 U/L before immunotherapy were 0.404 (95% confidence interval [CI]: 0.207-0.791, P = .008), 2.753 (95%CI: 1.127-6.455, P = .026) and 2.469 (95%CI: 1.155-5.277, P = .020), respectively. Hypothyroidism was associated with prognosis in patients with HCC treated with PD-1 inhibitors, and prognosis was more favourable in patients with hypothyroidism than in those without hypothyroidism. Hypothyroidism and the Child-Pugh grade at initial admission were independently associated with patient prognosis. 10.1002/ijc.33813
    Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy in Hepatocellular Carcinoma: Where Do We Stand? Rizzo Alessandro,Ricci Angela Dalia,Di Federico Alessandro,Frega Giorgio,Palloni Andrea,Tavolari Simona,Brandi Giovanni Frontiers in oncology Hepatocellular carcinoma (HCC) remains the sixth most commonly diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Over the next few years, novel systemic treatment options have emerged. Among these, immune checkpoint inhibitors (ICIs) have been widely evaluated and are under assessment, as monotherapy or in combination with other anticancer agents in treatment-naïve and previously treated patients. In particular, the approval of the PD-L1 inhibitor atezolizumab plus the antiangiogenic agent bevacizumab as front-line treatment for advanced HCC has led to the adoption of this combination in this setting, and the IMbrave 150 phase III trial has established a novel standard of care. However, several questions remain unanswered, including the identification of reliable predictors of response to ICIs in HCC patients. In the current paper, we will provide an updated overview of potentially useful predictive biomarkers of response to immunotherapy in advanced HCC. A literature search was conducted in September 2021 of Pubmed/Medline, Cochrane library and Scopus databases. 10.3389/fonc.2021.803133
    PD-L1, TMB, and other potential predictors of response to immunotherapy for hepatocellular carcinoma: how can they assist drug clinical trials? Expert opinion on investigational drugs INTRODUCTION:Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed malignancy worldwide, accounting for millions of deaths annually. Despite immune checkpoint inhibitors (ICIs) reported important results, only a minority of HCC patients benefit from these treatments, and the identification of predictive biomarkers of response still remains a highly unmet need. AREAS COVERED:Herein, we provide a timely overview of available evidence on biochemical predictors of response to immunotherapy in advanced HCC patients; we speculate on how PD-L1, TMB, and other emerging biomarkers could assist drug clinical trials in the near future. A literature search was conducted in June 2021 using Pubmed/Medline, Cochrane library, and Scopus databases. EXPERT OPINION:Reliable predictors of response to ICIs are of pivotal importance to allow a proper stratification and selection of HCC patients that could derive more benefit from immunotherapy. Well-designed, multicenter clinical trials specifically focused on predictive biomarkers are warranted in this setting, where most of evidence currently derives from retrospective, single-center studies with small sample size. 10.1080/13543784.2021.1972969
    Expanding the immunotherapy roadmap for hepatocellular carcinoma. Cancer cell In a recent Lancet Oncology article, Yau et al. report the CheckMate 459 trial results. This is the first phase III trial comparing the single-agent anti-programmed death protein 1 (PD-1) therapy nivolumab to the tyrosine kinase inhibitor sorafenib for treatment-naive patients with advanced hepatocellular carcinoma. 10.1016/j.ccell.2022.02.017
    Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody. Liver cancer INTRODUCTION:Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC. METHODS:Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in β-catenin and those without the mutations using transcriptome-based immunogram. RESULTS:Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein < 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8 cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8 tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS ( < 0.0001 and = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γ response, inhibitory molecules, and regulatory T cells. DISCUSSION/CONCLUSION:The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8 TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI. 10.1159/000516899
    Mechanistic Rationales Guiding Combination Hepatocellular Carcinoma Therapies Involving Immune Checkpoint Inhibitors. Cheu Jacinth Wing-Sum,Wong Carmen Chak-Lui Hepatology (Baltimore, Md.) Hepatocellular carcinoma (HCC) is one of the deadliest cancers because of late symptom manifestation leading to delayed diagnosis, which limits patients with HCC in terms of receiving curative surgical treatment. There are only a few therapeutic options for patients with advanced HCC. The emergence of immune checkpoint inhibitors (ICIs) brings HCC treatment to a stage at which nivolumab, an anti-programmed cell death protein 1 monoclonal antibody, achieves a 20% response rate. However, the large proportion of unresponsive patients drives the exploration of therapeutic strategies to improve ICIs' efficacy. Recent preclinical and clinical studies have suggested that ICIs, when used in combinations or when used with other cancer therapies, might elicit synergistic antitumor effects. However, the mechanistic rationales guiding different drug combinations to maximize this synergy remain largely ambiguous. In this review, we discuss different drug combinations used in HCC and the underlying mechanistic rationales, aiming to enhance the understanding of how these treatments can achieve synergy. This knowledge sets the foundation for the development of more effective and promising combination therapies for HCC. 10.1002/hep.31840
    Gender-specific Stratification of Survival Following Immune Checkpoint Inhibitor Therapy Based on Intratumoral Expression of a B cell Gene Signature. European urology oncology BACKGROUND:There is a great need to identify biomarkers that can accurately identify patients who will obtain the most clinical benefit from immune checkpoint inhibitor (ICI) therapy. While high intratumoral B cell gene expression correlated with an ICI response in melanoma, whether it adds predictive value in other cancers is unknown. OBJECTIVE:To examine the relationship between B cell gene signature (BCGS) expression and overall survival (OS) following ICI treatment. DESIGN, SETTING, AND PARTICIPANTS:A total of 348 patients with advanced urothelial carcinoma from the IMvigor 210 phase 2 clinical trial of atezolizumab and 406 patients with muscle-invasive bladder cancer from The Cancer Genome Atlas (TCGA) were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:We analyzed tumor RNA sequencing data of included patients to examine the relationships between a BCGS and clinical outcomes. RESULTS AND LIMITATIONS:Tumors with high levels of B cell and CD8+ T cell gene signatures (BCGS/CD8TGS or B8T high/high) were associated with the longest OS of all B8T groups. Moreover, the B8T cell signature stratified patients whose tumors had a high tumor mutational burden or high programmed death ligand 1 (PD-L1) into subsets with differential OS outcomes. Whereas the B8T high/high tumors were associated with the best clinical outcomes in ICI-treated men, they were not associated with better OS in women. Conversely, women with B8T high/high tumors had the best clinical outcomes in non-ICI-treated muscle-invasive bladder cancer. CONCLUSIONS:These data suggest that the B8T signature can enhance OS stratification in patients with advanced urothelial carcinoma who are treated with ICI therapy and that sex-specific differences in the tumor immune microenvironment may drive disparate outcomes. PATIENT SUMMARY:We examined whether the presence of two immune cell gene signatures within tumor samples impact survival in patients with bladder cancer. High levels of both of these signatures (B cells and CD8+ T cells) associate with superior survival in patients who receive immune therapy. 10.1016/j.euo.2021.07.003
    PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Zou Weiping,Wolchok Jedd D,Chen Lieping Science translational medicine PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota. We further clarify the mechanisms of action of these markers and their roles in shaping, being shaped, and/or predicting therapeutic responses. We also discuss a variety of combinations with PD pathway blockade and their scientific rationales for cancer treatment. 10.1126/scitranslmed.aad7118
    Biomarkers of response to PD-1 pathway blockade. British journal of cancer The binding of T cell immune checkpoint proteins programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to their ligands allows immune evasion by tumours. The development of therapeutic antibodies, termed checkpoint inhibitors, that bind these molecules or their ligands, has provided a means to release this brake on the host anti-tumour immune response. However, these drugs are costly, are associated with potentially severe side effects, and only benefit a small subset of patients. It is therefore important to identify biomarkers that discriminate between responders and non-responders. This review discusses the determinants for a successful response to antibodies that bind PD-1 or its ligand PD-L1, dividing them into markers found in the tumour biopsy and those in non-tumour samples. It provides an update on the established predictive biomarkers (tumour PD-L1 expression, tumour mismatch repair deficiency and tumour mutational burden) and assesses the evidence for new potential biomarkers. 10.1038/s41416-022-01743-4
    Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial. Nature communications The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab. 10.1038/s41467-022-29441-y
    Exploring Markers of Exhausted CD8 T Cells to Predict Response to Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma. Liver cancer BACKGROUND:Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. OBJECTIVES:The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). METHODS:Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. RESULTS:HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy ( = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8LAG3 cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors ( = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. CONCLUSIONS:CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC. 10.1159/000515305
    Analysis of multispectral imaging with the AstroPath platform informs efficacy of PD-1 blockade. Science (New York, N.Y.) Next-generation tissue-based biomarkers for immunotherapy will likely include the simultaneous analysis of multiple cell types and their spatial interactions, as well as distinct expression patterns of immunoregulatory molecules. Here, we introduce a comprehensive platform for multispectral imaging and mapping of multiple parameters in tumor tissue sections with high-fidelity single-cell resolution. Image analysis and data handling components were drawn from the field of astronomy. Using this "AstroPath" whole-slide platform and only six markers, we identified key features in pretreatment melanoma specimens that predicted response to anti-programmed cell death-1 (PD-1)-based therapy, including CD163PD-L1 myeloid cells and CD8FoxP3PD-1 T cells. These features were combined to stratify long-term survival after anti-PD-1 blockade. This signature was validated in an independent cohort of patients with melanoma from a different institution. 10.1126/science.aba2609
    A novel signature based on pairwise PD-1/PD-L1 signaling pathway genes for predicting the overall survival in patients with hepatocellular carcinoma. Zhao Enfa,Chen Shimin,Dang Ying Clinical and translational medicine 10.1002/ctm2.431
    Immune Checkpoint Inhibitors in Combinations for Hepatocellular Carcinoma. Kalasekar Sharanya Maanasi,Garrido-Laguna Ignacio,Evason Kimberley Jane Hepatology (Baltimore, Md.) 10.1002/hep.31706
    Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma. Rizzo Alessandro,Brandi Giovanni Cancer treatment and research communications Hepatocellular carcinoma (HCC) represents the most commonly diagnosed liver cancer worldwide, and the overall survival of patients with unresectable disease is poor. In the last five years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment scenario of several hematological and solid tumors, and these agents have been actively explored in unresectable HCC. Firstly, promising findings of phase I and II clinical studies reporting durable responses and a tolerable safety profile have led to the assessment of ICIs as single agents in phase III clinical studies; however, the latter have provided controversial results, and the activity of ICI monotherapy seems limited to a small subgroup of patients. Conversely, the IMbrave150 trial recently showed that, among patients with previously untreated unresectable HCC, treatment with atezolizumab plus bevacizumab resulted in significantly longer overall survival and progression-free survival compared to sorafenib monotherapy. In addition, the activity of several other ICIs is under investigation, as combination immunotherapy as well as combinations of immunotherapy with antiangiogenic agents. Nonetheless, there are currently no validated predictive biomarkers able to guide treatment choice in this setting, where the identification of specific predictors of response to ICIs represents a major challenge. In this review, we aim to provide a critical overview of recent evidence on biochemical predictors of response to ICIs in patients with unresectable HCC, especially focusing on PD-L1, TMB, MSI, and other emerging biomarkers. 10.1016/j.ctarc.2021.100328
    PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease. International journal of molecular sciences Non-alcoholic fatty liver disease (NAFLD) is characterized by an enhanced activation of the immune system, which predispose the evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Resident macrophages and leukocytes exert a key role in the pathogenesis of NAFLD. In particular, CD4+ effector T cells are activated during the early stages of liver inflammation and are followed by the increase of natural killer T cells and of CD8+ T cytotoxic lymphocytes which contribute to auto-aggressive tissue damage. To counteract T cells activation, programmed cell death 1 (PD-1) and its ligand PDL-1 are exposed respectively on lymphocytes and liver cells' surface and can be targeted for therapy by using specific monoclonal antibodies, such as of Nivolumab, Pembrolizumab, and Atezolizumab. Despite the combination of Atezolizumab and Bevacizumab has been approved for the treatment of advanced HCC, PD-1/PD-L1 blockage treatment has not been approved for NAFLD and adjuvant immunotherapy does not seem to improve survival of patients with early-stage HCC. In this regard, different ongoing phase III trials are testing the efficacy of anti-PD-1/PD-L1 antibodies in HCC patients as first line therapy and in combination with other treatments. However, in the context of NAFLD, immune checkpoints inhibitors may not improve HCC prognosis, even worse leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Here, we will describe the main pathogenetic mechanisms which characterize the immune system involvement in NAFLD discussing advantages and obstacles of anti PD-1/PDL-1 immunotherapy. 10.3390/ijms23052707
    NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature Hepatocellular carcinoma (HCC) can have viral or non-viral causes. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need. Here we report the progressive accumulation of exhausted, unconventionally activated CD8PD1 T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8PD1 T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8PD1CXCR6, TOX, and TNF T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 T cells or TNF neutralization, suggesting that CD8 T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8PD1 T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment. 10.1038/s41586-021-03362-0
    Liver fibrosis promotes immune escape in hepatocellular carcinoma via GOLM1-mediated PD-L1 upregulation. Ke Meng-Yun,Xu Tao,Fang Yi,Ye Yuan-Peng,Li Zhi-Jin,Ren Feng-Gang,Lu Shao-Ying,Zhang Xu-Feng,Wu Rong-Qian,Lv Yi,Dong Jian Cancer letters Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, with the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC), the challenges facing the application of this treatment are tremendous. Liver fibrosis is a key driver of tumor immune escape, the underlying mechanism has never been clarified. This study sought to explore the role of liver fibrosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression. Ninety-nine fixed HCC tissue samples were used to analyze the association between liver fibrosis and immune escape using immunohistochemistry. In HCC patients, low FIB-4 values and high CD8 T cell infiltration were correlated with prolonged survival. Elevated expression of immune checkpoints and attenuated antitumor immunity were observed in CCl-induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with fibrosis and mice in response to CCl-induced liver fibrosis. CD8 T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) inducing chemical carcinogenesis compared to their corresponding control WT mice. GOLM1 induced PD-L1 expression via EGFR pathway activation. EGFR inhibitors, especially together with anti-PD-L1 therapy, improved the efficacy of immunotherapy in HCC. These findings illustrate the importance of liver fibrosis-induced immunosuppression as a tumor-promoting mechanism. GOLM1, which is highly upregulated in the fibrotic liver, regulates tumor microenvironmental immune escape via the EGFR/PD-L1 signaling pathway. EGFR blockade may bolster the efficacy of immune checkpoint inhibitors for HCC treatment. 10.1016/j.canlet.2021.05.007
    The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma. Cellular & molecular immunology BACKGROUND:The efficacy of immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) or its ligand 1 (PD-L1) antibody, in hepatocellular carcinoma (HCC) is limited, and it is recommended that they be combined with other therapies. We evaluated the combination of pegylated interferon-α (Peg-IFNα) with PD-1 blockade in HCC mouse models. METHODS:We analyzed the effects of Peg-IFNα on tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway. The in vivo efficacy of anti-PD-1 and Peg-IFNα was evaluated in both subcutaneous and orthotopic mouse models of HCC. RESULTS:The combination of Peg-IFNα with PD-1 blockade dramatically enhanced T-cell infiltration, improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy. Mechanistically, Peg-IFNα could recruit cytotoxic CD8 T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4. Nevertheless, the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8 T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway. The combination of PD-1 blockade with Peg-IFNα could restore the cytotoxic capacity of CD8 T cells and exerted a significant synergistic effect on HCC. CONCLUSION:These results indicate that in addition to initiating the antitumor immune response itself, Peg-IFNα can also generate a microenvironment favoring PD-1 blockade. Thus, the combination of Peg-IFNα and PD-1 blockade can be a promising strategy for HCC. 10.1038/s41423-022-00848-3
    The Influence of Immune Heterogeneity on the Effectiveness of Immune Checkpoint Inhibitors in Multifocal Hepatocellular Carcinomas. Huang Manling,He Minghui,Guo Yu,Li Heping,Shen Shunli,Xie Yubin,Li Xiaoxing,Xiao Han,Fang Lujing,Li Dongming,Peng Baogang,Liang Lijian,Yu Jun,Kuang Ming,Xu Lixia,Peng Sui Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:Immune checkpoint inhibitor therapy is emerging as the promising option for patients with advanced hepatocellular carcinoma. We aimed to investigate the heterogeneity of different tumor nodules of the same patient with multifocal hepatocellular carcinomas in response to immunotherapy and its molecular mechanisms. EXPERIMENTAL DESIGN:We attained 45 surgical tumor samples including 33 small and 12 large nodules from 12 patients with multifocal hepatocellular carcinoma and evaluated genomic and immune heterogeneity among tumors through whole-genome sequencing and RNA sequencing. IHC was performed to validate the expression of immune markers. The responses to anti-programmed cell death protein-1 (PD-1) therapy in patients with multifocal hepatocellular carcinoma were evaluated. RESULTS:The small and large tumors within the same patient presented with similar genomic characteristics, indicating their same genomic origin. We further found the small tumors had higher immune cell infiltration including more CD8 T cells, M1 macrophages, and monocytes as compared with large tumors. Besides, the expression of interferon signature predictive of response to anti-PD-1 therapy was significantly upregulated in the small tumors. Moreover, the immune pathways were more vigorous along with less active proliferation pathways in the small tumors. In keeping with this, we found that small nodules were more sensitive to anti-PD-1 therapy than large nodules in patients with multifocal hepatocellular carcinoma. CONCLUSIONS:The small tumors in patients with multifocal hepatocellular carcinoma had higher immune cell infiltration and upregulation of immune pathways as compared with the large tumors, which can partially explain the different responses of small and large tumors in the same case to anti-PD-1 therapy. 10.1158/1078-0432.CCR-19-3840
    Dynamics of Serum Tumor Markers Can Serve as a Prognostic Biomarker for Chinese Advanced Non-small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors. Zhang Zhibo,Yuan Fang,Chen Runzhe,Li Ye,Ma Junxun,Yan Xiang,Wang Lijie,Zhang Fan,Tao Haitao,Guo Dong,Huang Zhiyue,Zhang Sujie,Li Xiaoyan,Zhi Xiaoyu,Ge Xiangwei,Hu Yi,Wang Jinliang Frontiers in immunology Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers were associated with the efficacy and prognosis of Chinese late-stage NSCLC patients treated with programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors. We initiated a longitudinal prospective study on advanced NSCLC patients treated with PD-1/PD-L1 inhibitors in Chinese PLA general hospital (Beijing, China). Blood samples of baseline and after 6 weeks' treatment were collected. CT scan were used by all patients to evaluate treatment efficacy according to RECIST 1.1. Serum tumor markers levels were measured with an electrochemical luminescence for SCC-Ag and with a chemiluminescent microparticle immunoassay for serum CEA, CA125, and CYFRA21-1. At least 20% decreases of the biomarkers from baseline were considered as meaningful improvements after 6 weeks of treatment with immune checkpoint inhibitors (ICIs). Optimization-based method was used to balance baseline covariates between different groups. Associations between serum tumor biomarker improvements and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed. A total of 308 Chinese patients with advanced NSCLC were enrolled in the study. After balancing baseline covariates, patients with meaningful improvements in <2 out of 4 biomarkers (CEA, CA125, CYFRA21-1, and SCC-Ag) was ended up with lower ORR (0.08 vs. 0.35, < 0.001), shorten PFS (median: 5.4 vs. 12.5 months, < 0.001), and OS (median: 11.7 vs. 25.6 months, < 0.001) in the total population. Subgroup analysis of patients with adenocarcinoma revealed that patients with meaningful improvements in <2 out of 4 biomarkers had significant lower ORR (0.06 vs. 0.36, < 0.001), shorten PFS (median: 4.1 vs. 11.9 months, < 0.001), and OS (median: 11.9 vs. 24.2 months, < 0.001). So as in patients with squamous cell carcinoma, meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs. 0.08, = 0.014), longer PFS (median: 13.1 vs. 5.6 months, = 0.001), and OS (median: 25.6 vs. 10.9 months, = 0.06). The dynamic change of CEA, CA125, CYFRA21-1, and SCC-Ag from baseline have prognostic value for late-stage NSCLC patients treated with PD-1/PD-L1 inhibitors. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes. 10.3389/fimmu.2020.01173
    Identification and Utilization of Biomarkers to Predict Response to Immune Checkpoint Inhibitors. Gjoerup Ole,Brown Charlotte A,Ross Jeffrey S,Huang Richard S P,Schrock Alexa,Creeden James,Fabrizio David,Tolba Khaled The AAPS journal Immune checkpoint inhibitors (ICPI) have revolutionized cancer therapy and provided clinical benefit to thousands of patients. Despite durable responses in many tumor types, the majority of patients either fail to respond at all or develop resistance to the ICPI. Furthermore, ICPI treatment can be accompanied by serious adverse effects. There is an urgent need for identification of patient populations that will benefit from ICPI as single agents and when used in combinations. As ICPI have achieved regulatory approvals, accompanying biomarkers including PD-L1 immunohistochemistry (IHC) and tumor mutational burden (TMB) have also received approvals for some indications. The ICPI pembrolizumab was the first example of a tissue-agnostic FDA approval based on tumor microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarker status, rather than on tumor histology assessment. Several other ICPI-associated biomarkers are in the exploratory stage, including quantification of tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP) of an inflamed microenvironment, and neoantigen prediction. TMB and PD-L1 expression can predict a subset of responses, but they fail to predict all responses to checkpoint blockade. While a single biomarker is currently limited in its ability to fully capture the complexity of the tumor-immune microenvironment, a combination of biomarkers is emerging as a method to improve predictive power. Here we review the steadily growing impact of comprehensive genomic profiling (CGP) for development and utilization of predictive biomarkers by simultaneously capturing TMB, MSI, and the status of genomic targets that confer sensitivity or resistance to immunotherapy, as well as detecting inflammation through RNA expression signatures. 10.1208/s12248-020-00514-4
    Novel Biomarkers of Dynamic Blood PD-L1 Expression for Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer Patients. Yang Qiao,Chen Mingjing,Gu Jiaoyang,Niu Kai,Zhao Xianlan,Zheng Linpeng,Xu Zihan,Yu Yongxin,Li Feng,Meng Lingxin,Chen Zhengtang,Zhuo Wenlei,Zhang Luping,Sun Jianguo Frontiers in immunology Background:Immune checkpoint inhibitors (ICIs) have become a high-profile regimen for malignancy recently. However, only a small subpopulation obtains long-term clinical benefit. How to select optimal patients by reasonable biomarkers remains a hot topic. Methods:Paired tissue samples and blood samples from 51 patients with advanced malignancies were collected for correlation analysis. Dynamic changes in blood PD-L1 (bPD-L1) expression, including PD-L1 mRNA, exosomal PD-L1 (exoPD-L1) protein and soluble PD-L1 (sPD-L1), were detected after 2 months of ICIs treatment in advanced non-small-cell lung cancer (NSCLC) patients. The best cutoff values for progression-free survival (PFS) and overall survival (OS) of all three biomarkers were calculated with R software. Results:In 51 cases of various malignancies, those with positive tissue PD-L1 (tPD-L1) had significantly higher PD-L1 mRNA than those with negative tPD-L1. In 40 advanced NSCLC patients, those with a fold change of PD-L1 mRNA ≥ 2.04 had better PFS, OS and best objective response (bOR) rate. In addition, a fold change of exoPD-L1 ≥ 1.86 was also found to be associated with better efficacy and OS in a cohort of 21 advanced NSCLC cases. The dynamic change of sPD-L1 was not associated with efficacy and OS. Furthermore, the combination of PD-L1 mRNA and exoPD-L1 could screen better patients for potential benefit from ICIs treatment. Conclusion:There was a positive correlation between bPD-L1 and tPD-L1 expression. Increased expression of PD-L1 mRNA, exoPD-L1, or both in early stage of ICIs treatment could serve as positive biomarkers of efficacy and OS in advanced NSCLC patients. 10.3389/fimmu.2021.665133
    Predictive biomarkers for response to immune checkpoint inhibitors in lung cancer: PD-L1 and beyond. Uruga Hironori,Mino-Kenudson Mari Virchows Archiv : an international journal of pathology Immune checkpoint inhibitor (ICI) therapies, including the programmed cell death protein 1 (PD-1) axis blockade, are considered a major oncological breakthrough of the early twenty-first century and have led to remarkable response rates and survival in a subset of patients with non-small cell lung cancer (NSCLC). However, the available therapies work only for one in five unselected, advanced NSCLC patients; thus, patient selection needs to be performed with the use of efficient biomarkers. Although imperfect, programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) on tumor cells and/or immune cells has been established as a predictive biomarker for response to the PD-1 axis blockade. There remain several pre-analytical, analytical, and post-analytical issues, however, before implementing a PD-L1 IHC assay(s) in the pathology laboratory. In addition, given the lack of robust sensitivity and specificity of PD-L1 IHC for predicting response to ICIs, other biomarkers including tumor mutation burden (TMB) are under investigation. In this review, issues associated with PD-L1 IHC and TMB estimations will be discussed, and other promising biomarkers for predicting response to ICIs will be briefly introduced. 10.1007/s00428-021-03030-8
    PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Doroshow Deborah Blythe,Bhalla Sheena,Beasley Mary Beth,Sholl Lynette M,Kerr Keith M,Gnjatic Sacha,Wistuba Ignacio I,Rimm David L,Tsao Ming Sound,Hirsch Fred R Nature reviews. Clinical oncology Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20-40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1 disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours. 10.1038/s41571-021-00473-5
    Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. Mao Jinzhu,Wang Dongxu,Long Junyu,Yang Xu,Lin Jianzhen,Song Yiwei,Xie Fucun,Xun Ziyu,Wang Yanyu,Wang Yunchao,Li Yiran,Sun Huishan,Xue Jingnan,Song Yang,Zuo Bangyou,Zhang Junwei,Bian Jin,Zhang Ting,Yang Xiaobo,Zhang Lei,Sang Xinting,Zhao Haitao Journal for immunotherapy of cancer BACKGROUND:The gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers. METHODS:Patients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy. RESULTS:In total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance. CONCLUSIONS:We demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signatures enriched in responders are effective biomarkers to predict the clinical response and survival benefit of immunotherapy, which might provide a new therapeutic target to modulate the response to cancer immunotherapy. 10.1136/jitc-2021-003334
    Transarterial chemoembolisation enhances programmed death-1 and programmed death-ligand 1 expression in hepatocellular carcinoma. Montasser Ahmed,Beaufrère Aurélie,Cauchy François,Bouattour Mohamed,Soubrane Olivier,Albuquerque Miguel,Paradis Valérie Histopathology AIMS:Immunotherapies represent a new alternative therapeutic approach for hepatocellular carcinomas (HCCs), and have shown promising results when used in combination therapy. The aim of this study was to evaluate the potential of transarterial chemoembolisation (TACE) to modulate programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression profiles in a cohort of surgically treated HCCs. METHODS AND RESULTS:A total of 82 surgically treated HCCs from patients who had undergone (n = 32) or not undergone (n = 50) preoperative TACE were included in the study. Immunohistochemical expression of PD-1 and of PD-L1 were analysed and compared according to TACE treatment. Pretreatment biopsies, which were available for 30 cases (20 with TACE and 10 without), were similarly analysed. Follow-up data were retrieved from patients' charts. PD-1 expression (≥1%) in intratumoral inflammatory cells (ICs) was observed in 46% of HCCs, and PD-L1 expression (≥1%) in ICs and PD-L1 expression in tumour cells (TCs) were observed in 46% and 16% of HCCs, respectively. A low level of PD-1 expression (<1%) was associated with strong and diffuse glutamine synthetase overexpression (8% versus 27%, P = 0.024). HCCs from patients with TACE pretreatment showed significantly higher PD-L1 expression in TCs than those from patients without TACE pretreatment (2% versus 0.4%, P = 0.027). PD-1 expression in ICs and PD-L1 expression in both ICs and TCs were higher in TACE-resected tumours than in corresponding pre-TACE biopsies (respectively: 1.8% versus 8.1%, P = 0.034; 0.8% versus 7.1%, P = 0.032; and 0% versus 2.4%, P = 0.043). CONCLUSION:Our results, showing increases in PD-1 expression and PD-L1 expression in HCCs following TACE, support the use of TACE in combination with immunotherapy in selected cases to optimise tumour response. 10.1111/his.14317
    New insights into checkpoint inhibitor immunotherapy and its combined therapies in hepatocellular carcinoma: from mechanisms to clinical trials. International journal of biological sciences Hepatocellular carcinoma (HCC) is one of the most lethal tumors in China and worldwide, although first-line therapies for HCC, such as atezolizumab and bevacizumab, have been effective with good results, the researches on new therapies have attracted much attention. With the deepening research on tumor immunology, the role and operation mechanism of immune cells in the tumor microenvironment (TME) of HCC have been explained, such as programmed cell death protein 1 (PD-1) binding to ligand could cause T cell exhaustion and reduce IFN-γ T cell secretion, cytotoxic T lymphocyte 4 (CTLA-4) and CD28 mediate immunosuppression by competing for B7 protein and disrupting CD28 signal transduction pathway, which also lays the foundation for the development and application of more new immune checkpoint inhibitors (ICIs). The biological behavior of various immune checkpoints has been proved in HCC, such as PD-1, programmed cell death ligand 1 (PD-L1), CTLA-4 and so on, leading to a series of clinical trials. Currently, FDA approved nivolumab, pembrolizumab and nivolumab plus ipilimumab for the treatment of HCC. However, the treatment of ICI has the disadvantages of low response rate and many side effects, so the combination of ICIs and various other therapies (such as VEGF or VEGFR inhibition, neoadjuvant and adjuvant therapy, locoregional therapies) has been derived. Further studies on immune checkpoint mechanisms may reveal new therapeutic targets and new combination therapies in the future. 10.7150/ijbs.70691
    Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma. Langhans Bettina,Nischalke Hans Dieter,Krämer Benjamin,Dold Leona,Lutz Philipp,Mohr Raphael,Vogt Annabelle,Toma Marieta,Eis-Hübinger Anna Maria,Nattermann Jacob,Strassburg Christian P,Gonzalez-Carmona Maria Angeles,Spengler Ulrich Cancer immunology, immunotherapy : CII Immune checkpoint inhibition suggests promising progress for the treatment of advanced hepatocellular carcinoma (HCC). However, the underlying cellular mechanisms remain unclear because liver cancer cells apparently do not upregulate inhibitory checkpoint molecules. Here, we analysed whether regulatory T cells (Tregs) can alternatively trigger checkpoint inhibition pathways in HCC. Using flow cytometry we analysed expression of checkpoint molecules (PD-1, PD-L1, CTLA-4, GITR, Tim-3) on peripheral CD4CD25Foxp3 Tregs and their secretion of inhibitory mediators (IL-10, IL-35, TGF-beta, galectin-9) in 116 individuals (50 patients with HCC, 41 non-tumour bearing liver disease controls, 25 healthy controls). Functional activity of Tregs on T effector cells (IFN-gamma production, cytotoxicity) was characterized in vitro using a lectin-dependent cellular cytotoxicity (LDCC) assay against checkpoint inhibitor-negative P815 target cells. Unlike liver patients without malignancy and healthy controls, the frequency of checkpoint inhibitor-positive Tregs inversely correlated to age of patients with HCC (PD-L1, p = 0.0080; CTLA-4, p = 0.0029) and corresponded to enhanced numbers of Tregs producing IL-10 and IL-35 (p < 0.05 each). Tregs inhibited IFN-gamma secretion and cytotoxicity of CD8 T cells when added to LDCC against P815 cells. Treg-induced inhibition of IFN-gamma secretion could be partially blocked by neutralizing PD-1 and PD-L1 antibodies specifically in HCC patients. In HCC peripheral Tregs upregulate checkpoint inhibitors and contribute to systemic immune dysfunction and antitumoural activity by several inhibitory pathways, presumably facilitating tumour development at young age. Blocking PD-L1/PD-1 interactions in vitro selectively interfered with inhibitory Treg -T effector cell interactions in the patients with HCC and resulted in improved antitumoural activity also against checkpoint inhibitor-negative tumour cells. 10.1007/s00262-019-02427-4
    Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy. Schweizer Claudia,Schubert Philipp,Rutzner Sandra,Eckstein Markus,Haderlein Marlen,Lettmaier Sebastian,Semrau Sabine,Gostian Antoniu-Oreste,Frey Benjamin,Gaipl Udo S,Zhou Jian-Guo,Fietkau Rainer,Hecht Markus European journal of cancer (Oxford, England : 1990) BACKGROUND:Prospective data about the prognostic value of immune-related adverse events (irAEs) in non-melanoma solid tumours are rare. The prognostic value of irAEs in patients treated with combined radiotherapy and immunotherapy is currently unknown. PATIENTS AND METHODS:The prospective non-interventional ST-ICI trial investigates treatment response of tumour patients to anti-programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors alone and in combination with radiotherapy and possible predictive markers. Patients undergoing immunotherapy or immunoradiotherapy were surveyed for irAEs. RESULTS:A total of 104 patients were included of whom 29 patients (28%) developed irAEs. Additional radiotherapy was performed in 50 patients (48%). Main tumour entities within the entire cohort were non-small cell lung cancer (NSCLC) (44%) and head and neck squamous cell carcinoma (42%). The rate of irAEs did not differ in patients with and without radiotherapy (p = 0.668). Patients who developed irAEs had longer overall survival (OS) (median: 22.8 months versus 9.0 months without irAEs, p = 0.001) and progression-free survival (PFS) (median: 7.8 months versus 3.2 months without irAEs, p = 0.002). In the subgroup with combined radiotherapy, patients with irAEs also had longer OS (median: 22.8 months versus 7.1 months without irAEs, p = 0.005) and PFS (median: 8.8 months versus 3.0 months without irAEs, p = 0.005). On multivariate analysis only PD-L1 on tumour cells (p = 0.049) and irAEs (p = 0.001) remained independent predictors of OS. CONCLUSION:The development of irAEs represents a favourable prognostic parameter in patients undergoing immunotherapy and immunoradiotherapy for solid tumours. 10.1016/j.ejca.2020.09.001
    Correlation Between Immune-Related Adverse Events and Prognosis in Hepatocellular Carcinoma Patients Treated With Immune Checkpoint Inhibitors. Xu Shuo,Lai Ruixue,Zhao Qian,Zhao Pandong,Zhao Ruili,Guo Zhanjun Frontiers in immunology Background:Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were associated with clinical benefit in cancer patients of melanoma, a lung cancer. In the present study, we investigated the correlation between irAE and ICI efficacy in hepatocellular carcinoma (HCC) patients. Methods:We divided the HCC patients who received the anti-PD-1 antibody into two groups as irAE group and non-irAE group according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. The treatment efficacy of ICIs was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Result:Of the 65 HCC patients who received the anti-PD-1 antibody (monotherapy or combined with targeted medicine), median PFS in the irAE group was superior to that in the non-irAE group (302 days vs. 148 days, = 0.004). Median OS in the irAE group was also better than that in the non-irAE group (374 days vs. 279 days, = 0.038). Although the statistical difference for DCR in the irAE group and non-irAE group was not reached, the DCR of the irAE displayed a trend better than that of the non-irAE group (41.20% vs. 20.80%, = 0.118). Multivariate analysis also demonstrated that the non-irAE group (HR = 6.410, 95% CI: 1.404 to 29.275) was associated independently with the poor prognosis. Conclusions:Development of irAEs was associated with clinical benefit for HCC patients who were treated with immune checkpoint inhibitors; irAE, particularly low-grade irAE, was a predictable marker for better ICI treatment efficiency in HCC patients. 10.3389/fimmu.2021.794099
    Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study. Bonaventura Aldo,Grossi Francesco,Carbone Federico,Vecchié Alessandra,Minetti Silvia,Bardi Nicholas,Elia Edoardo,Ansaldo Anna Maria,Ferrara Daniele,Rijavec Erika,Dal Bello Maria Giovanna,Rossi Giovanni,Biello Federica,Tagliamento Marco,Alama Angela,Coco Simona,Spallarossa Paolo,Dallegri Franco,Genova Carlo,Montecucco Fabrizio Cancer immunology, immunotherapy : CII Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results. 10.1007/s00262-019-02367-z
    Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC. Carbone Federico,Ministrini Stefano,Bonaventura Aldo,Vecchié Alessandra,Minetti Silvia,Bardi Nicholas,Elia Edoardo,Ansaldo Anna Maria,Ferrara Daniele,Rijavec Erika,Dal Bello Maria Giovanna,Biello Federico,Rossi Giovanni,Tagliamento Marco,Alama Angela,Coco Simona,Spallarossa Paolo,Grossi Francesco,Genova Carlo,Montecucco Fabrizio European journal of clinical investigation BACKGROUND:High circulating levels of cellular adhesion molecules (CAMs) in non-small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre-treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC. MATERIALS AND METHODS:Seventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow-up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival ≥2 years or absence of disease progression at the end of the follow-up, and the overall survival. RESULTS:Composite outcome and overall survival were positively associated with VCAM-1 baseline levels and with the reduction of VCAM-1 during the treatment. After adjustment for potential confounders, the change in VCAM-1 serum levels during the treatment was an independent predictor of overall survival. CONCLUSIONS:High baseline serum levels of VCAM-1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy. 10.1111/eci.13668
    Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab. Oyanagi Jun,Koh Yasuhiro,Sato Koichi,Mori Keita,Teraoka Shunsuke,Akamatsu Hiroaki,Kanai Kuninobu,Hayata Atsushi,Tokudome Nahomi,Akamatsu Keiichiro,Nakanishi Masanori,Ueda Hiroki,Yamamoto Nobuyuki Lung cancer (Amsterdam, Netherlands) BACKGROUND:Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers. PATIENTS AND METHODS:Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated. RESULTS:Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-α levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE. CONCLUSION:Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms. 10.1016/j.lungcan.2019.03.020
    Clinical utility of the C-reactive protein:albumin ratio in non-small cell lung cancer patients treated with nivolumab. Araki Taisuke,Tateishi Kazunari,Sonehara Kei,Hirota Shuko,Komatsu Masamichi,Yamamoto Manabu,Kanda Shintaro,Kuraishi Hiroshi,Hanaoka Masayuki,Koizumi Tomonobu Thoracic cancer BACKGROUND:Nivolumab is a second-line chemotherapy for non-small cell lung cancer (NSCLC). This study explored the impact of clinical biomarkers such as neutrophil:lymphocyte ratio (NLR), C-reactive protein:albumin ratio (CAR), and modified Glasgow prognostic score on the efficacy and outcome of nivolumab monotherapy in previously treated NSCLC patients. METHODS:We retrospectively analyzed advanced or postoperative recurrence of NSCLC in 113 patients in two Japanese facilities from January 2015 to December 2019. Optimal cutoff values of NLR and CAR were assessed by the area under the receiver operating characteristic curves predicting death events to conduct regression analysis. Baseline values and values collected eight weeks after nivolumab treatment were measured to investigate time-series changes of these markers. RESULTS:The patients showed median overall survival (OS) and progression-free survival (PFS) of 14.0 months and 2.3 months, respectively, with both being significantly longer in patients with partial response (PR) than in patients with progressive disease (PD). Optimal cutoff levels for NLR and CAR were 5.8 and 0.83, with significant decrease in CAR (P = 0.002) from baseline levels in PR patients and significant increase in PD patients. Baseline CAR ≥0.83 was significantly associated with one-year mortality events and overall survival (OS), and multivariate analysis showed significant association of age ≤70 years, an Eastern Cooperative Oncology Group performance status score of 2 or 3, and a baseline CAR ≥0.83 with inferior OS. CONCLUSIONS:For second-line nivolumab therapy, evaluation of baseline CAR and subsequent changes in CAR may be predictive of therapeutic response to nivolumab and long-term survival in NSCLC patients. KEY POINTS:Significant findings of the study The baseline value of C-reactive protein:albumin ratio was significantly associated with one-year mortality and overall survival in non-small cell lung cancer patients treated with nivolumab. What this study adds Time-series change of C-reactive protein:albumin ratio may be useful for predicting the treatment efficacy in patients treated with nivolumab. 10.1111/1759-7714.13788
    Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma. Jiang Guangyi,Shi Liang,Zheng Xueyong,Zhang Xinjie,Wu Ke,Liu Boqiang,Yan Peijian,Liang Xiao,Yu Tunan,Wang Yifan,Cai Xiujun Aging Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with gender-related differences in onset and course. Androgen receptor (AR), a male hormone receptor, is critical in the initiation and progression of HCC. The role of AR in HCC has been mechanistically characterized and anti-AR therapies have been developed, showing limited efficacy. Immunotherapy targeting immune checkpoint proteins may substantially improve the clinical management of HCC. The mechanism by which AR influences HCC immune state remains unclear. In this study, we demonstrated that AR negatively regulated PD-L1, by acting as a transcriptional repressor of PD-L1. Notably, AR over-expression in HCC cells enhanced CD8T function . We then verified the AR/PD-L1 correlation in patients. In animal experiment we found that lower AR expressed tumor achieved better response to PD-L1 inhibitor. Thus, AR suppressed PD-L1 expression, possibly contributing to gender disparity in HCC. Better understanding of the roles of AR during HCC initiation and progression will provide a novel angle to develop potential HCC immunotherapies. 10.18632/aging.103231
    Prognostic and predictive role of CD8 and PD-L1 determination in lung tumor tissue of patients under anti-PD-1 therapy. Fumet Jean-David,Richard Corentin,Ledys Fanny,Klopfenstein Quentin,Joubert Philippe,Routy Bertrand,Truntzer Caroline,Gagné Andréanne,Hamel Marc-André,Guimaraes Camila Figueiredo,Coudert Bruno,Arnould Laurent,Favier Laure,Lagrange Aurélie,Ladoire Sylvain,Saintigny Pierre,Ortiz-Cuaran Sandra,Perol Maurice,Foucher Pascal,Hofman Paul,Ilie Marius,Chevrier Sandy,Boidot Romain,Derangere Valentin,Ghiringhelli François British journal of cancer BACKGROUND:No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non-small-cell lung cancer (NSCLC). METHODS:We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types. RESULTS:In prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures. CONCLUSION:CD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles. 10.1038/s41416-018-0220-9
    Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA oncology IMPORTANCE:Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. OBJECTIVE:To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. DESIGN, SETTING, AND PARTICIPANTS:CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). INTERVENTIONS:Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). MAIN OUTCOMES AND MEASURES:Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). RESULTS:Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). CONCLUSIONS AND RELEVANCE:In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT01658878. 10.1001/jamaoncol.2020.4564
    Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study. Gane Edward,Verdon Daniel J,Brooks Anna E,Gaggar Anuj,Nguyen Anh Hoa,Subramanian G Mani,Schwabe Christian,Dunbar P Rod Journal of hepatology BACKGROUND & AIMS:To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV. METHODS:In a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24. RESULTS:There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75-77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI -0.46 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log by the end of study. One patient, whose HBsAg went from baseline 1,173 IU/ml to undetectable at week 20, experienced an alanine aminotransferase flare (grade 3) at week 4 that resolved by week 8 and was accompanied by a significant increase in peripheral HBsAg-specific T cells at week 24. CONCLUSIONS:In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient. LAY SUMMARY:Chronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB. Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527. 10.1016/j.jhep.2019.06.028
    TMB and Inflammatory Gene Expression Associated with Clinical Outcomes following Immunotherapy in Advanced Melanoma. Hodi F Stephen,Wolchok Jedd D,Schadendorf Dirk,Larkin James,Long Georgina V,Qian Xiaozhong,Saci Abdel,Young Tina C,Srinivasan Sujaya,Chang Han,Tang Hao,Wind-Rotolo Megan,Rizzo Jasmine I,Jackson Donald G,Ascierto Paolo A Cancer immunology research Outcomes for patients with melanoma have improved over the past decade as a result of the development and FDA approval of immunotherapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1). However, these therapies do not benefit all patients, and an area of intensive research investigation is identifying biomarkers that can predict which patients are most likely to benefit from them. Here, we report exploratory analyses of the associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and mutation status with tumor response, progression-free survival, and overall survival in patients with advanced melanoma treated as part of the CheckMate 066 and 067 phase III clinical trials evaluating immuno-oncology therapies. In patients enrolled in CheckMate 067 receiving the anti-PD-1 inhibitor nivolumab (NIVO) alone or in combination with the anti-CTLA-4 inhibitor ipilimumab (IPI) or IPI alone, longer survival appeared to associate with high (>median) versus low (≤median) TMB and with high versus low inflammatory signature scores. For NIVO-treated patients, the results regarding TMB association were confirmed in CheckMate 066. In addition, improved survival was observed with high TMB and absence of mutation. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Combined assessment of TMB, inflammatory gene expression signature, and mutation status may be predictive for response to immune checkpoint blockade in advanced melanoma. 10.1158/2326-6066.CIR-20-0983
    ARID1A Deficiency Is Associated With High Programmed Death Ligand 1 Expression in Hepatocellular Carcinoma. Iseda Norifumi,Itoh Shinji,Yoshizumi Tomoharu,Yugawa Kyohei,Morinaga Akinari,Tomiyama Takahiro,Toshima Takeo,Kohashi Kenichi,Oda Yoshinao,Mori Masaki Hepatology communications The clinicopathological features of carcinomas expressing AT-rich interaction domain 1a (ARID1A) and programmed death ligand 1 (PD-L1) in HCC are poorly understood. Here, we examined ARID1A and PD-L1 expression in surgically resected primary hepatocellular carcinoma (HCC) and the association of ARID1A and PD-L1 expression with clinicopathological features and patient outcomes. Their association with ARID1A expression and tumor-associated CD68-positive macrophage was further explored. Using a database of 255 patients who underwent hepatic resection for HCC, immunohistochemical staining of ARID1A, PD-L1, and CD68 was performed. We also analyzed the expression PD-L1 after ARID1A knockdown in HCC cell lines. Samples from 81 patients (31.7%) were negative for ARID1A. Negative ARID1A expression was significantly associated with male sex, high alpha-fetoprotein, high des-gamma-carboxyprothrombin, large tumor size, high rate of poor differentiation, microscopic intrahepatic metastasis, and PD-L1 expression. In addition, negative ARID1A expression was an independent predictor for recurrence-free survival, overall survival, and positive PD-L1 expression. Stratification based on ARID1A and PD-L1 expression in cancer cells was also significantly associated with unfavorable outcomes. PD-L1 protein expression levels were increased through phosphoinositide 3-kinase/AKT signaling after ARID1A knockdown in HCC cells. HCC with ARID1A-low expression was significantly correlated with high levels of tumor-associated CD68-positive macrophage. Our large cohort study showed that ARID1A expression in cancer cells was associated with a poor clinical outcome in patients with HCC, PD-L1 expression in cancer cells, and tumor microenvironment. Therefore, ARID1A may be a potential molecular biomarker for the selection of patients with HCC for anti-programmed death 1/PD-L1 antibody therapy. 10.1002/hep4.1659
    Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti-Programmed Cell Death-1 in HCC. Yi Chenhe,Chen Lirong,Lin Zhifei,Liu Lu,Shao Weiqing,Zhang Rui,Lin Jing,Zhang Jubo,Zhu Wenwei,Jia Huliang,Qin Lunxiu,Lu Lu,Chen Jinhong Hepatology (Baltimore, Md.) BACKGROUND AND AIMS:Recently, clinical trials of lenvatinib plus pembrolizumab in HCC have displayed an impressive objective response rate. This study aimed to clarify the mechanism for optimal patient selection. APPROACH AND RESULTS:First, in patients with HCC, lenvatinib-treated recurrent tumors had lower programmed death ligand 1 (PD-L1) expression and regulatory T cell (Treg) infiltration compared with matched primary tumors. Consistently, in C57BL/6 wild-type mice receiving anti-programmed cell death 1 (PD-1) therapy, PD-L1 expression and Treg infiltration in s.c. tumors were reduced when adding lenvatinib to the scheme. Mechanistically, on the one hand, FGF receptor 4 (FGFR4) was the most pivotal target in PD-L1 down-regulation by lenvatinib in vitro. Furthermore, lenvatinib reinforced the proteasomal degradation of PD-L1 by blocking the FGFR4-glycogen synthase kinase 3β axis and rescued the sensitivity of interferon-γ-pretreated HCC cells to T-cell killing by targeting FGFR4. On the other hand, the level of IL-2 increased after anti-PD-1 treatment, but IL-2-mediated Treg differentiation was blocked by lenvatinib through targeting FGFR4 to restrain signal transducer and activator of transcription 5 (STAT5) phosphorylation. By regulating the variations in the number of Tregs and the tumor FGFR4 level in C57BL/6-forkhead box protein P3 (Foxp3 ) mice, we found that high levels of FGFR4 and Treg infiltration sensitized tumors to the combination treatment. Finally, high levels of FGFR4 and Foxp3 conferred immune tolerance but better response to the combined therapy in patient cohorts. CONCLUSIONS:Lenvatinib reduced tumor PD-L1 level and Treg differentiation to improve anti-PD-1 efficacy by blocking FGFR4. Levels of FGFR4 expression and Treg infiltration in tumor could serve as biomarkers for screening patients with HCC using lenvatinib plus anti-PD-1 combination therapy. 10.1002/hep.31921
    Characterization of the Immune Microenvironment in Hepatocellular Carcinoma. Yarchoan Mark,Xing Dongmei,Luan Lan,Xu Haiying,Sharma Rajni B,Popovic Aleksandra,Pawlik Timothy M,Kim Amy K,Zhu Qingfeng,Jaffee Elizabeth M,Taube Janis M,Anders Robert A Clinical cancer research : an official journal of the American Association for Cancer Research Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies. To characterize the immune microenvironment in HCC, IHC staining was performed for CD8-positive T lymphocytes, PD-1-positive, and LAG-3-positive lymphocytes, CD163-positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC. Expression of CD8 was reduced in tumor, and expression of CD163 was reduced at the tumor interface. Positive clusters of PD-L1 expression were identified in 24 of 29 cases (83%), and positive expression of LAG-3 on tumor-infiltrating lymphocytes was identified in 19 of 29 cases (65%). The expression of both PD-L1 and LAG-3 was increased in tumor relative to liver background. No association between viral status or other clinicopathologic features and expression of any of the IHC markers investigated was noted. LAG-3 and PD-L1, two inhibitory molecules implicated in CD8 T-cell tolerance, are increased in most HCC tumors, providing a basis for investigating combinatorial checkpoint blockade with a LAG-3 and PD-L1 inhibitor in HCC. . 10.1158/1078-0432.CCR-17-0950
    Efficacy of Cabozantinib and Nivolumab in Treating Hepatocellular Carcinoma with RET Amplification, High Tumor Mutational Burden, and PD-L1 Expression. Yang Xiaobo,Shi Junping,Chen Xiaoqian,Jiang Yan,Zhao Haitao The oncologist We report on a patient with hepatocellular carcinoma (HCC) who developed bone metastasis after surgery. RET amplification, high tumor mutational burden (TMB; TMB ≥10 mutations per megabase), and programmed death-ligand 1 (PD-L1) expression were detected by next-generation sequencing. Oral administration of cabozantinib was initiated. Nivolumab was added after 1 month. The patient responded well to cabozantinib and nivolumab therapy, with tolerated adverse reactions, and achieved progression-free survival of more than 25 months. To the best of our knowledge, this is the first clinical case report in the literature to describe the benefit of cabozantinib and nivolumab treatment in a patient with HCC and RET amplification, high TMB, and positive PD-L1 expression. This study explored the selection of biomarkers for targeted therapy and combination immunotherapy in patients with HCC. KEY POINTS: A patient with metastatic hepatocellular carcinoma (HCC) harboring RET amplification, high tumor mutational burden, and positive programmed death-ligand 1 expression responded well to the combination of cabozantinib and nivolumab therapy with progression-free survival of longer than 25 months. The combination of nivolumab and cabozantinib may be a good option for patients with advanced HCC, especially those with bone metastasis. The efficacy of cabozantinib and immune checkpoint inhibitors suggests the necessity of the combined application of multiple detection technologies, including next-generation sequencing and immunohistochemistry, for patients with HCC. This study explored the selection of biomarkers for targeted therapy and combination immunotherapy for patients with HCC. 10.1634/theoncologist.2019-0563
    PD-L1 polymorphisms predict survival outcomes in advanced non-small-cell lung cancer patients treated with PD-1 blockade. Yoshida Hironori,Nomizo Takashi,Ozasa Hiroaki,Tsuji Takahiro,Funazo Tomoko,Yasuda Yuto,Ajimizu Hitomi,Yamazoe Masatoshi,Kuninaga Kiyomitsu,Ogimoto Tatsuya,Hosoya Kazutaka,Itotani Ryo,Sakamori Yuichi,Kim Young Hak,Hirai Toyohiro European journal of cancer (Oxford, England : 1990) BACKGROUND:We previously reported that PD-L1 polymorphisms are associated with the efficacy and immune-related adverse events of PD-1 blockade with nivolumab. However, the association between PD-L1 polymorphisms and survival outcomes under PD-1/PD-L1 blockade is still uncertain. Here, we aimed to investigate whether PD-L1 polymorphisms are associated with survival outcomes in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab. METHODS:PD-1/PD-L1 polymorphisms and survival outcomes were retrospectively analysed in two independent cohorts (133 patients treated with nivolumab and 96 patients with no treatment history of an immune checkpoint inhibitor (ICI) (the non-ICI cohort)) with advanced NSCLC. RESULTS:Among the 7 studied single-nucleotide polymorphisms, PD-L1 rs822339 and rs1411262 were associated with overall survival (OS) in patients treated with nivolumab. Patients with the A/A genotype of rs822339 had a significantly longer OS than those with A/G or G/G genotypes (not reached versus 12.0 months; hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.18-0.64; p = 0.0008). A similar survival benefit with the A/A genotype was observed regardless of driver mutation status. In multivariate analysis, performance status (PS) and PD-L1 rs822339 genotype were independent prognostic factors for OS. In the non-ICI cohort, the PD-L1 rs822339 genotype did not correlate with OS (HR, 0.77; 95% CI, 0.31-1.70; p = 0.55). The T/T genotype of rs1411262 also showed a significant prolongation of OS compared to that with the C/T or C/C genotypes in patients treated with nivolumab. CONCLUSIONS:PD-L1 polymorphisms are associated with favourable OS in nivolumab-treated NSCLC patients and may be useful predictive biomarkers, regardless of driver mutation status. 10.1016/j.ejca.2020.11.035
    Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes. Cao Di,Chen Meng-Ke,Zhang Qing-Feng,Zhou Yu-Feng,Zhang Mei-Yin,Mai Shi-Juan,Zhang Yao-Jun,Chen Min-Shan,Li Xiao-Xing,Wang Hui-Yun Aging Recent studies demonstrate that immune checkpoint inhibitor (ICI) therapy has achieved success in many types of advanced cancers including advanced hepatocellular carcinoma (HCC). However, ICI therapy is beneficial in only some HCC patients, suggesting that immune-responses are highly variable in HCCs. Therefore, understanding the immune status in HCC microenvironment will facilitate ICI immunotherapy and guide patient selection for the therapy. In this study, we first analyzed the expression profile of immune-modulating genes and their relationship with survival of HCC patients using the data downloaded from The Cancer Genome Atlas - Liver Hepatocellular Carcinoma (TCGA-LIHC) database, and found that the higher expressions of CD276 (B7-H3) and CD47 were significantly associated with poor survival. Then we identified 4 immune subtypes of HCCs with different survivals by using the combination expression of B7-H3 (or CD47) and CD8. Patients with B7-H3/CD8 or CD47/CD8 have the best survival while ones with B7-H3/CD8 or CD47/CD8 have the worst survival. The 4 immune subtypes were validated in another 72 HCC patients obtained from South China. In conclusion, our findings suggest that HCC patient prognosis is associated with immunophenotypes by T cell infiltration (CD8 expression) and the expression of the adaptive immune resistance gene (B7-H3 or CD47), and this immune classification system will facilitate HCC patient selection for ICI immunotherapy. 10.18632/aging.103395
    Peritumoural CCL1 and CCL22 expressing cells in hepatocellular carcinomas shape the tumour immune infiltrate. Wiedemann Gabriela M,Röhrle Natascha,Makeschin Marie-Christine,Fesseler Julia,Endres Stefan,Mayr Doris,Anz David Pathology Development, course of disease and prognosis of hepatocellular carcinomas (HCC) are strongly influenced by the immune system. Immunosuppressive regulatory T cells (Treg) have been shown to negatively impact disease progression and survival. To further understand the mechanisms of Treg attraction to HCC lesions, this study provides an analysis of Treg attracting chemokines in human HCC tissues. We analysed the expression of the Treg attracting chemokines CCL1 and CCL22 as well as the infiltration of FoxP3+ Treg and CD8+ T cells in paraffin-embedded tissue sections of 62 HCC patients. Expression of both chemokines was detected in 47 of 62 tissue slides. Chemokine expression was generally higher in tumour stroma and peritumoural liver tissue than in the tumour tissue itself. CD8+ T cells and FoxP3+ Treg were found at high levels in many tumour tissues. Intratumoural infiltration of Treg positively correlated with CCL22 levels in peritumoural liver tissue. In contrast, no correlation of Treg numbers and expression of CCL1 was detected. In summary, we describe here that the chemokines CCL1 and CCL22 are expressed in HCC tissues and, to a higher extent, in the stroma and peritumoural liver tissue. CCL22 may contribute to Treg recruitment and immunosuppression, whereas the role of CCL1 remains to be defined. It will be interesting to investigate the potential of these chemokines as drug targets for cancer therapy. 10.1016/j.pathol.2019.06.001
    An Integrated Analysis of the Identified PRPF19 as an Onco-immunological Biomarker Encompassing the Tumor Microenvironment, Disease Progression, and Prognoses in Hepatocellular Carcinoma. Yang Ming,Qiu Yiwen,Yang Yi,Wang Wentao Frontiers in cell and developmental biology Targeting the mRNA splicing process has been identified as a therapeutic strategy for human cancer. PRPF19 is an RNA binding protein that is involved in pre-mRNA processing and repairing DNA damage; the aberrant expression of PRPF19 is potentially associated with carcinogenesis. However, the biological role of PRPF19 in hepatocellular carcinoma (HCC) is still elusive. Data obtained from TCGA, Oncomine, and GEO were used to investigate the PRPF19 expression level and its role in tumor immune infiltration, prognosis, and the tumor progression of cohorts from HCC. Using various databases and tools (UALCAN, TIMER, TISMO, and PathCards), we presented the potential mechanisms of PFPF19 upregulation, PRPF19-related pathways, and its biological functions in liver cancer. For HCC, PRPF19 expression was found upregulated both in single tumor cells and tissues. Furthermore, the increased expression of PRPF19 was significantly correlated to clinical characteristics: advanced stage, vascular invasion, high AFP, and poor prognosis of HCC. According to the tumor-immunological analysis, we found that PRPF19 is positively correlated with infiltrating myeloid-derived suppressor cells (MDSCs). Moreover, the microenvironment of HCC tissues with high expression of PRPF19 is highly immunosuppressive (lower T-lymphocytes, multiple immune checkpoints upregulated). Patients with high expression of PRPF19 and high MDSCs had a worse survival prognosis as well. TP53 mutation may have a positive effect on PRPF19 expression decreased promoter methylation of PRPF19. By TF-mRNA network analysis, key transcription factors (TFs) in TC-NER and PCS pathways (PRPF19 involved) were identified. This work implied that PRPF19 is associated with tumor immune evasion and progression, and serves as a prognostic marker for worse clinical outcomes with HCC. Thus, this critical regulator could serve as a potential therapeutic target of HCC. 10.3389/fcell.2022.840010
    Progression on the Roles and Mechanisms of Tumor-Infiltrating T Lymphocytes in Patients With Hepatocellular Carcinoma. Zheng Xiaoqin,Jin Wenjie,Wang Shanshan,Ding Huiguo Frontiers in immunology Primary liver cancer (PLC) is one of the most common malignancies in China, where it ranks second in mortality and fifth in morbidity. Currently, liver transplantation, hepatic tumor resection, radiofrequency ablation, and molecular-targeted agents are the major treatments for hepatocellular carcinoma (HCC). Overall, HCC has a poor survival rate and a high recurrence rate. Tumor-infiltrating lymphocytes (TILs) have been discovered to play essential roles in the development, prognosis, and immunotherapy treatment of HCC. As the major component cells of TILs, T cells are also proved to show antitumor and protumor effects in HCC. Foxp3+, CD8+, CD3+, and CD4+ T lymphocytes are the broadly studied subgroups of TILs. This article reviews the roles and mechanisms of different tumor-infiltrating T lymphocyte subtypes in HCC. 10.3389/fimmu.2021.729705
    Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC. Gabrielson Andrew,Wu Yunan,Wang Hongkun,Jiang Jiji,Kallakury Bhaskar,Gatalica Zoran,Reddy Sandeep,Kleiner David,Fishbein Thomas,Johnson Lynt,Island Eddie,Satoskar Rohit,Banovac Filip,Jha Reena,Kachhela Jaydeep,Feng Perry,Zhang Tiger,Tesfaye Anteneh,Prins Petra,Loffredo Christopher,Marshall John,Weiner Louis,Atkins Michael,He Aiwu Ruth Cancer immunology research Immune cells that infiltrate a tumor may be a prognostic factor for patients who have had surgically resected hepatocellular carcinoma (HCC). The density of intratumoral total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was measured in the tumor interior and in the invasive margin of 65 stage I to IV HCC tissue specimens from a single cohort. Immune cell density in the interior and margin was converted to a binary score (0, low; 1, high), which was correlated with tumor recurrence and relapse-free survival (RFS). In addition, the expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) was correlated with the density of CD3(+) and CD8(+) cells and clinical outcome. High densities of both CD3(+) and CD8(+) T cells in both the interior and margin, along with corresponding Immunoscores, were significantly associated with a low rate of recurrence (P = 0.007) and a prolonged RFS (P = 0.002). In multivariate logistic regression models adjusted for vascular invasion and cellular differentiation, both CD3(+) and CD8(+) cell densities predicted recurrence, with odds ratios of 5.8 [95% confidence interval (CI), 1.6-21.8] for CD3(+) and 3.9 (95% CI, 1.1-14.1) for CD8(+) Positive PD-L1 staining was correlated with high CD3 and CD8 density (P = 0.024 and 0.005, respectively) and predicted a lower rate of recurrence (P = 0.034), as well as prolonged RFS (P = 0.029). Immunoscore and PD-L1 expression, therefore, are useful prognostic markers in patients with HCC who have undergone primary tumor resection. Cancer Immunol Res; 4(5); 419-30. ©2016 AACR. 10.1158/2326-6066.CIR-15-0110
    Clinicopathological and Prognostic Value of Programmed Cell Death 1 Expression in Hepatitis B Virus-related Hepatocellular Carcinoma: A Meta-analysis. Journal of clinical and translational hepatology BACKGROUND AND AIMS:The efficacy of targeted programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs) has been confirmed in many solid malignant tumors. The overexpression of PD-1/PD-L1 serves as a biomarker to predict prognosis and clinical progression. However, the role of PD-1 in patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) remains indeterminate. Given that HBV is the most important cause for HCC, this study aimed to investigate the prognostic and clinicopathological value of PD-1 in HBV-HCC via a meta-analysis. METHODS:We searched PubMed, Embase, Scopus, the Cochrane Library, Web of Science and Google Scholar up to January 2021 for studies on the correlation between clinicopathology/prognosis and PD-1 in patients with HBV-HCC. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to investigate the prognostic significance of PD-1 expression. The odds ratios (ORs) and 95% CIs were determined to explore the association between PD-1 expression and clinicopathological features. RESULTS:Our analysis included seven studies with 658 patients, which showed that high PD-1 expression was statistically correlated with poorer overall survival (HR=2.188, 95% CI: [1.262-3.115], <0.001) and disease-free survival (HR=2.743, 95% CI: [1.980-3.506], <0.001). PD-1 overexpression was correlated with multiple tumors (OR=2.268, 95% CI: [1.209-4.257], =0.011), high level of alpha fetoprotein (AFP; OR=1.495, 95% CI: [1.005-2.223], =0.047) and advanced Barcelona Clinic Liver Cancer (BCLC) stage (OR=3.738, 95% CI: [2.101-6.651], <0.001). CONCLUSIONS:Our meta-analysis revealed that the high level of PD-1 expression was associated with multiple tumors, high level of AFP and advanced BCLC stage. It significantly predicted a poor prognosis of HBV-HCC, which suggests that anti-PD-1 therapy for HBV-HCC patients is plausible. 10.14218/JCTH.2021.00056
    Clinicopathologic Significance and Prognostic Value of Programmed Cell Death Ligand 1 (PD-L1) in Patients With Hepatocellular Carcinoma: A Meta-Analysis. Li Jing-Hua,Ma Wei-Jie,Wang Gang-Gang,Jiang Xiang,Chen Xi,Wu Long,Liu Zhi-Su,Zeng Xian-Tao,Zhou Fu-Ling,Yuan Yu-Feng Frontiers in immunology There is still a dispute over an issue of the clinical pathology and prognostic of programmed cell death ligand 1 (PD-L1) in hepatocellular carcinoma (HCC) patients. Here, we undertook this meta-analysis to survey the conceivable role of PD-L1 in HCC. We searched databases like MEDLINE, EMBASE, and Google Scholar for relevant studies published in English up to February 13, 2018. We implemented the appraisal of the eligible studies according to the choice criterion. We used Hazard ratio (HR) and its 95% confidence interval (95% CI) to evaluate the prognostic role of PD-L1 for overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS). Odds ratio (OR) and the corresponding 95% CI were calculated to evaluate the connection between PD-L1 and clinicopathological features. Publication bias was tested. 13 studies, which published range from 2009 to 2017 were contained in this meta-analysis, involving 1,843 patients with HCC. The results indicated that high PD-L1 could predict shorter OS (HR = 1.57, 95% CI: 1.09-2.27, < 0.00001) as well as poorer DFS (HR = 2.07, 95% CI: 1.20-3.58, = 0.009). Additionally, high PD-L1 expression was correlated to liver cirrhosis (OR = 1.66, 95% CI: 1.10-2.50, = 0.02), poorer tumor Barcelona Clinical Liver Cancer (BCLC) stage (OR = 0.30, 95% CI: 0.10-0.88, = 0.03) and portal vein invasion (OR = 1.96, 95% CI: 1.04-3.68, = 0.04), but had no correlation with age, gender, tumor size, number of tumors, AFP, vascular invasion, HBVs-Ag, Anti-HCV, differentiation or TNM stage. Besides, no significant publication bias was found among these identified studies. The meta-analysis suggested that PD-L1 overexpression could foresee worse OS and DFS in HCC. Moreover, the PD-L1 expression has to bear on liver cirrhosis, portal vein invasion, and BCLC stage. 10.3389/fimmu.2018.02077
    Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis. Li Xiao-Song,Li Jun-Wei,Li Hui,Jiang Tao Bioscience reports The prognostic role of programmed death ligand-1 (PD-L1) expression in hepatocellular carcinoma (HCC) has been widely studied but the results are controversial. In this comprehensive meta-analysis, we elucidated the clinical value of PD-L1 in HCC. Relevant studies were systematically searched in the Cochrane Library, EMBASE, and PubMed until June 27, 2019. Eligible studies were validated for the prognostic effect of PD-L1 on the overall survival (OS), disease-free survival (DFS), and relapse-free survival (RFS) in HCC using a hazard ratio (HR) and its 95% confidence interval (95% CI). Twenty-three studies with 3529 patients were involved in this meta-analysis. The pooled results revealed that high membrane-bound PD-L1 (mPD-L1) expression was associated with poor OS (HR: 1.42; 95% CI: 1.12-1.80; P = 0.004) and had no significant correlation with RFS (HR: 1.14; 95% CI: 0.85-1.54; P = 0.39), and DFS (HR: 1.36; 95% CI: 0.81-2.28; P = 0.25). The results also indicated that high soluble PD-L1 (sPD-L1) levels were associated with worse OS (HR: 2.93; 95% CI: 2.20-3.91; P < 0.00001). In addition, high mPD-L1 expression was associated with high alpha-fetoprotein levels (AFP; OR = 1.46; 95% CI: 1.16-1.84; P = 0.001), hepatitis (OR = 0.72; 95% CI: 0.54-0.98; P = 0.03), poor tumor differentiation (OR = 0.68; 95% CI: 0.55-0.84; P = 0.03), and tumor-infiltrating lymphocytes (OR = 3.39; 95% CI: 1.06-10.91; P = 0.04). The mPD-L1 expression had no significant correlation with age, number of tumors, gender, tumor size, liver cirrhosis, vascular invasion, tumor encapsulation, or TNM stage. The study revealed that high mPD-L1 expression in the tumor tissue and high sPD-L1 levels were associated with shorter OS in HCC. Moreover, overexpression of mPD-L1 was significantly associated with poor tumor differentiation, hepatitis, AFP elevation, and tumor-infiltrating lymphocytes. 10.1042/BSR20200459
    Impact of Immune Response on Outcomes in Hepatocellular Carcinoma: Association With Vascular Formation. Itoh Shinji,Yoshizumi Tomoharu,Yugawa Kyohei,Imai Daisuke,Yoshiya Shohei,Takeishi Kazuki,Toshima Takeo,Harada Noboru,Ikegami Toru,Soejima Yuji,Kohashi Kenichi,Oda Yoshinao,Mori Masaki Hepatology (Baltimore, Md.) BACKGROUND AND AIMS:We investigated the prognostic value of programmed death ligand 1 (PD-L1) expression, tumor-infiltrating CD8-positive T-cell status, and their combination in hepatocellular carcinoma (HCC). Their association with PD-L1 expression and vascular formation was further explored. APPROACH AND RESULTS:Using a database of 387 patients who underwent hepatic resection for HCC, immunohistochemical staining of PD-L1, CD8, and CD34 was performed. Additionally, we undertook an enzyme-linked immunosorbent assay for soluble PD-L1. Compared with patients with HCC and PD-L1-negative expression (n = 311), patients with HCC and PD-L1-positive expression (n = 76) showed significantly worse overall survival (OS; multivariate hazard ratio, 2.502; 95% confidence interval [CI], 1.716-3.649; P < 0.0001). The presence of tumor-infiltrating CD8-positive T cells was significantly correlated with longer OS (multivariate hazard ratio, 0.383; 95% CI, 0.274-0.537; P < 0.0001). Stratification based on PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status was also significantly associated with OS (log-rank, P < 0.0001). HCC with PD-L1-positive expression was significantly correlated with positivity for vessels that encapsulated tumor clusters. Serum PD-L1 levels were significantly higher in the group of patients who had PD-L1-positive expression than in the group of patients who had PD-L1-negative expression (P = 0.0158). CONCLUSIONS:PD-L1 expression in cancer cells was associated with a poor clinical outcome and vascular formation in patients with HCC. Additionally, the combination of PD-L1 expression with tumor-infiltrating CD8-positive T-cell status enabled further classification of patients based on their clinical outcome. Thus, PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status might serve as predictive tissue biomarkers. 10.1002/hep.31206
    Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. Ross-Macdonald Petra,Walsh Alice M,Chasalow Scott D,Ammar Ron,Papillon-Cavanagh Simon,Szabo Peter M,Choueiri Toni K,Sznol Mario,Wind-Rotolo Megan Journal for immunotherapy of cancer BACKGROUND:Nivolumab is an immune checkpoint inhibitor targeting the programmed death-1 receptor that improves survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). In contrast to other tumor types that respond to immunotherapy, factors such as programmed death ligand-1 (PD-L1) status and tumor mutational burden show limited predictive utility in ccRCC. To address this gap, we report here the first molecular characterization of nivolumab response using paired index lesions, before and during treatment of metastatic ccRCC. METHODS:We analyzed gene expression and T-cell receptor (TCR) clonality using lesion-paired biopsies provided in the CheckMate 009 trial and integrated the results with their PD-L1/CD4/CD8 status, genomic mutation status and serum cytokine assays. Statistical tests included linear mixed models, logistic regression models, Fisher's exact test, and Kruskal-Wallis rank-sum test. RESULTS:We identified transcripts related to response, both at baseline and on therapy, including several that are amenable to peripheral bioassays or to therapeutic intervention. At both timepoints, response was positively associated with T-cell infiltration but not associated with TCR clonality, and some non-Responders were highly infiltrated. Lower baseline T-cell infiltration correlated with elevated transcription of Wnt/β-catenin signaling components and hypoxia-regulated genes, including the Treg chemoattractant CCL28. On treatment, analysis of the non-responding patients whose tumors were highly T-cell infiltrated suggests association of the RIG-I-MDA5 pathway in their nivolumab resistance. We also analyzed our data using previous transcriptional classifications of ccRCC and found they concordantly identified a molecular subtype that has enhanced nivolumab response but is sunitinib-resistant. CONCLUSION:Our study describes molecular characteristics of response and resistance to nivolumab in patients with metastatic ccRCC, potentially impacting patient selection and first-line treatment decisions. TRIAL REGISTRATION NUMBER:NCT01358721. 10.1136/jitc-2020-001506
    Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Feun Lynn G,Li Ying-Ying,Wu Chunjing,Wangpaichitr Medhi,Jones Patricia D,Richman Stephen P,Madrazo Beatrice,Kwon Deukwoo,Garcia-Buitrago Monica,Martin Paul,Hosein Peter J,Savaraj Niramol Cancer BACKGROUND:Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response. METHODS:Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features. RESULTS:A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-β levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10. CONCLUSIONS:Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-β could be a predictive biomarker for response to pembrolizumab. 10.1002/cncr.32339
    Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatocellular carcinoma. Liu Chao-Qun,Xu Jing,Zhou Zhong-Guo,Jin Li-Lian,Yu Xing-Juan,Xiao Gang,Lin Jie,Zhuang Shi-Mei,Zhang Yao-Jun,Zheng Limin British journal of cancer BACKGROUND:Recent clinical studies have suggested that programmed death ligand 1 (PD-L1) expression in a tumour could be a potential biomarker for PD-L1/PD-1 blockade therapies. METHODS:To better characterise PD-L1 expression in hepatocellular carcinoma (HCC), we analysed its expression patterns in 453 HCC patients by double staining for CD68 and PD-L1 using the Tyramide Signal Amplification Systems combined with immunohistochemistry. We also investigated its correlation with clinical features, prognosis and immune status. RESULTS:The results showed that PD-L1 expression on tumour cells (TCs) was negatively associated with patients' overall survival (OS; P = 0.001) and relapse-free survival (RFS; P = 0.006); however, PD-L1 expression on macrophages (Mφs) was positively correlated with OS (P = 0.017). Multivariate analysis revealed that PD-L1 expression on TCs and Mφs were both independent prognostic factors for OS (hazard ratio (HR) = 1.168, P = 0.004 for TC-PD-L1; HR = 0.708, P = 0.003 for Mφ-PD-L1). Further studies showed that Mφ-PD-L1 tumours exhibited an activated immune microenvironment, with high levels of CD8 T-cell infiltration and immune-related gene expression. CONCLUSION:Our study provided a novel methodology to evaluate PD-L1 expression in the tumour microenvironment, which might help to select patients who would benefit from anti-PD-1/PD-L1 immunotherapies. 10.1038/s41416-018-0144-4
    Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma. Chen Dong-Ping,Ning Wan-Ru,Jiang Ze-Zhou,Peng Zhi-Peng,Zhu Ling-Yan,Zhuang Shi-Mei,Kuang Dong-Ming,Zheng Limin,Wu Yan Journal of hepatology BACKGROUND & AIMS:Programmed cell death 1 ligand 1 (PD-L1) expression on antigen-presenting cells is essential for T cell impairment, and PD-L1-expressing macrophages may mechanistically shape and therapeutically predict the clinical efficacy of PD-L1 or programmed cell death 1 blockade. We aimed to elucidate the mechanisms underlying PD-L1 upregulation in human tumor microenvironments, which remain poorly understood despite the clinical success of immune checkpoint inhibitors. METHODS:Monocytes/macrophages were purified from peripheral blood, non-tumor, or paired tumor tissues of patients with hepatocellular carcinoma (HCC), and their possible glycolytic switch was evaluated. The underlying regulatory mechanisms and clinical significance of metabolic switching were studied with both ex vivo analyses and in vitro experiments. RESULTS:We found that monocytes significantly enhanced the levels of glycolysis at the peritumoral region of human HCC. The activation of glycolysis induced PD-L1 expression on these cells and subsequently attenuated cytotoxic T lymphocyte responses in tumor tissues. Mechanistically, tumor-derived soluble factors, including hyaluronan fragments, induced the upregulation of a key glycolytic enzyme, PFKFB3, in tumor-associated monocytes. This enzyme not only modulated the cellular metabolic switch but also mediated the increased expression of PD-L1 by activating the nuclear factor kappa B signaling pathway in these cells. Consistently, the levels of PFKFB3CD68 cell infiltration in peritumoral tissues were negatively correlated with overall survival and could serve as an independent prognostic factor for survival in patients with HCC. CONCLUSIONS:Our results reveal a mechanism by which the cellular metabolic switch regulates the pro-tumor functions of monocytes in a specific human tumor microenvironment. PFKFB3 in both cancer cells and tumor-associated monocytes is a potential therapeutic target in human HCC. LAY SUMMARY:Programmed cell death 1 ligand 1 (PD-L1) expressed on antigen-presenting cells, rather than tumor cells, has been reported to play an essential role in checkpoint blockade therapy. A fundamental understanding of mechanisms that regulate the expression of PD-L1 on tumor-infiltrating monocytes/macrophages will undoubtedly lead to the possibility of developing novel PD-L1 blockade strategies with high specificity and efficiency. The current study unveils a novel mechanism by which metabolic switching links immune activation responses to immune tolerance in the tumor milieu, identifying potential targets for future immune-based anti-cancer therapies. 10.1016/j.jhep.2019.04.007
    CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. Kudo Masatoshi,Matilla Ana,Santoro Armando,Melero Ignacio,Gracián Antonio Cubillo,Acosta-Rivera Mirelis,Choo Su-Pin,El-Khoueiry Anthony B,Kuromatsu Ryoko,El-Rayes Bassel,Numata Kazushi,Itoh Yoshito,Di Costanzo Francesco,Crysler Oxana,Reig Maria,Shen Yun,Neely Jaclyn,Tschaika Marina,Wisniewski Tami,Sangro Bruno Journal of hepatology BACKGROUND & AIMS:Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. METHODS:This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS:Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. CONCLUSIONS:Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. LAY SUMMARY:In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. CLINICAL TRIAL NUMBER:NCT01658878. 10.1016/j.jhep.2021.04.047
    The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma. Chang Boyang,Huang Tao,Wei Huajun,Shen Lujun,Zhu Duo,He Wenjun,Chen Qifeng,Zhang Huihua,Li Yunjian,Huang Ruopan,Li Wang,Wu Peihong Cancer immunology, immunotherapy : CII BACKGROUND:Blocking the programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in hepatocellular carcinoma (HCC) is a very promising approach in immunotherapy. However, the correlation and prognostic values of serum soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have not been explored conjointly in HCC patients. METHODS:This study retrospectively included 120 HCC patients receiving radical resection. The serum levels of sPD-1/sPD-L1 and inflammatory cytokines were measured by antibody array assay. Immunohistochemistry was applied to assess both the expression of membrane-bound PD-L1, and the number of CD4 tumor-infiltrating lymphocytes (TILs) and CD8 TILs. RESULTS:The best cut-off values of sPD-1 and sPD-L1 for predicting disease-free survival (DFS) were 33.0 µg/ml and 11.2 µg/ml, respectively. Multivariable analysis showed that sPD-L1 was a negative independent prognostic factor [DFS, Hazard Ratio (HR) 2.58, 95% CI 1.14-5.84, P = 0.023; overall survival (OS), HR 1.77, 95% CI 1.01-3.12, P = 0.048], while sPD-1 was a favorable independent prognostic factor (DFS, HR 0.32, 95% CI 0.14-0.74, P = 0.007; OS, HR 0.54, 95% CI 0.30-0.98, P = 0.044) in HCC patients. We also observed some similar associations between inflammatory cytokines (IL-10, IL-17, TNF-α) and sPD-1 or sPD-L1, as well as a close positive association between sPD-1 and sPD-L1. No significant associations of sPD-1/sPD-L1 with either intra-tumoral PD-L1 expression, or the numbers of CD4 TILs and CD8 TILs were determined. CONCLUSIONS:Our findings indicate that sPD-1 and sPD-L1 are independent prognostic factors with opposite prognostic roles in predicting both DFS and OS in HCC patients. 10.1007/s00262-018-2271-4
    Disruption of SIRT7 Increases the Efficacy of Checkpoint Inhibitor via MEF2D Regulation of Programmed Cell Death 1 Ligand 1 in Hepatocellular Carcinoma Cells. Xiang Junyu,Zhang Ni,Sun Hui,Su Li,Zhang Chengcheng,Xu Huailong,Feng Juan,Wang Meiling,Chen Jun,Liu Limei,Shan Juanjuan,Shen Junjie,Yang Zhi,Wang Guiqin,Zhou Haijun,Prieto Jesus,Ávila Matías A,Liu Chungang,Qian Cheng Gastroenterology BACKGROUND & AIMS:Immune checkpoint inhibitors have some efficacy in the treatment of hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1), expressed on some cancer cells, binds to the receptor programmed cell death 1 (PDCD1, also called PD1) on T cells to prevent their proliferation and reduce the antigen-tumor immune response. Immune cells that infiltrate some types of HCCs secrete interferon gamma (IFNG). Some HCC cells express myocyte enhancer factor 2D (MEF2D), which has been associated with shorter survival times of patients. We studied whether HCC cell expression of MEF2D regulates expression of PD-L1 in response to IFNG. METHODS:We analyzed immune cells from 20 fresh HCC tissues by flow cytometry. We analyzed 225 fixed HCC tissues (from 2 cohorts) from patients in China by immunohistochemistry and obtained survival data. We created mice with liver-specific knockout of MEF2D (MEF2D mice). We knocked out or knocked down MEF2D, E1A binding protein p300 (p300), or sirtuin 7 (SIRT7) in SMMC-7721, Huh7, H22, and Hepa1-6 HCC cell lines, some incubated with IFNG. We analyzed liver tissues from mice and cell lines by RNA sequencing, immunoblot, dual luciferase reporter, and chromatin precipitation assays. MEF2D protein acetylation and proteins that interact with MEF2D were identified by coimmunoprecipitation and pull-down assays. H22 cells, with MEF2D knockout or without (controls), were transplanted into BALB/c mice, and some mice were given antibodies to deplete T cells. Mice bearing orthotopic tumors grown from HCC cells, with or without knockout of SIRT7, were given injections of an antibody against PD1. Growth of tumors was measured, and tumors were analyzed by immunohistochemistry and flow cytometry. RESULTS:In human HCC specimens, we found an inverse correlation between level of MEF2D and numbers of CD4 and CD8 T cells; level of MEF2D correlated with percentages of PD1-positive or TIM3-positive CD8 T cells. Knockout of MEF2D from H22 cells reduced their growth as allograft tumors in immune-competent mice but not in immune-deficient mice or mice with depletion of CD8 T cells. When MEF2D-knockout cells were injected into immune-competent mice, they formed smaller tumors that had increased infiltration and activation of T cells compared with control HCC cells. In human and mouse HCC cells, MEF2D knockdown or knockout reduced expression of PD-L1. MEF2D bound the promoter region of the CD274 gene (encodes PD-L1) and activated its transcription. Overexpression of p300 in HCC cells, or knockout of SIRT7, promoted acetylation of MEF2D and increased its binding, along with acetylated histones, to the promoter region of CD274. Exposure of HCC cells to IFNG induced expression of p300 and its binding MEF2D, which reduced the interaction between MEF2D and SIRT7. MEF2D-induced expression of PD-L1 upon IFNG exposure was independent of interferon-regulatory factors 1 or 9. In HCC cells not exposed to IFNG, SIRT7 formed a complex with MEF2D that attenuated expression of PD-L1. Knockout of SIRT7 reduced proliferation of HCC cells and growth of tumors in immune-deficient mice. Compared with allograft tumors grown from control HCC cells, in immune-competent mice, tumors grown from SIRT7-knockout HCC cells expressed higher levels of PD-L1 and had reduced infiltration and activation of T cells. In immune-competent mice given antibodies to PD1, allograft tumors grew more slowly from SIRT7-knockout HCC cells than from control HCC cells. CONCLUSIONS:Expression of MEF2D by HCC cells increases their expression of PD-L1, which prevents CD8 T-cell-mediated antitumor immunity. When HCC cells are exposed to IFNG, p300 acetylates MEF2D, causing it to bind the CD274 gene promoter and up-regulate PD-L1 expression. In addition to promoting HCC cell proliferation, SIRT7 reduced acetylation of MEF2D and expression of PD-L1 in HCC cells not exposed to IFNG. Strategies to manipulate this pathway might increase the efficacy of immune therapies for HCC. 10.1053/j.gastro.2019.10.025
    Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis. Yau Thomas,Hsu Chiun,Kim Tae-You,Choo Su-Pin,Kang Yoon-Koo,Hou Ming-Mo,Numata Kazushi,Yeo Winnie,Chopra Akhil,Ikeda Masafumi,Kuromatsu Ryoko,Moriguchi Michihisa,Chao Yee,Zhao Huanyu,Anderson Jeffrey,Cruz Christine Dela,Kudo Masatoshi Journal of hepatology BACKGROUND & AIMS:Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. METHODS:CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. RESULTS:There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. CONCLUSION:Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. LAY SUMMARY:The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878. 10.1016/j.jhep.2019.05.014
    Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Zhou Guoying,Sprengers Dave,Boor Patrick P C,Doukas Michail,Schutz Hannah,Mancham Shanta,Pedroza-Gonzalez Alexander,Polak Wojciech G,de Jonge Jeroen,Gaspersz Marcia,Dong Haidong,Thielemans Kris,Pan Qiuwei,IJzermans Jan N M,Bruno Marco J,Kwekkeboom Jaap Gastroenterology BACKGROUND & AIMS:Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non-small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 and CD8 T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. METHODS:We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 and CD4 T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. RESULTS:Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 and CD4 T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 TIL, compared with other CD8 TIL. Compared with TIL that did not express these inhibitory receptors, CD8 and CD4 TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 and CD4 TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. CONCLUSIONS:The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer. 10.1053/j.gastro.2017.06.017
    Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade. Zhu Ying,Yang Jing,Xu Da,Gao Xiao-Mei,Zhang Ze,Hsu Jennifer L,Li Chia-Wei,Lim Seung-Oe,Sheng Yuan-Yuan,Zhang Yu,Li Jian-Hua,Luo Qin,Zheng Yan,Zhao Yue,Lu Lu,Jia Hu-Liang,Hung Mien-Chie,Dong Qiong-Zhu,Qin Lun-Xiu Gut OBJECTIVE:In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models. DESIGN:We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and knockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC. RESULTS:The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPN tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8 T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC. CONCLUSIONS:OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC. 10.1136/gutjnl-2019-318419
    Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma. Ho Won Jin,Danilova Ludmila,Lim Su Jin,Verma Rohan,Xavier Stephanie,Leatherman James M,Sztein Marcelo B,Fertig Elana J,Wang Hao,Jaffee Elizabeth,Yarchoan Mark Journal for immunotherapy of cancer BACKGROUND AND AIMS:Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have clinical activity in hepatocellular carcinoma (HCC), but only a subset of patients respond to these therapies, highlighting a need for novel biomarkers to improve clinical benefit. HCC usually occurs in the setting of liver cirrhosis from chronic hepatitis B or C viral infection, but the effects of viral status on the tumor immune microenvironment and clinical responses to ICIs in HCC remains unclear. METHODS:We conducted a meta-analysis to estimate the objective response rates for PD-1/PD-L1 inhibitors in virally-infected and uninfected patients, and examined the effects of viral etiology on the tumor microenvironment using data from The Cancer Genome Atlas, as well as peripheral blood responses using an independent cohort of patients studied by mass cytometry (cytometry by time-of-flight (CyTOF)). RESULTS:Meta-analysis comparing objective response rates (ORR) between virally-infected and uninfected patients showed no clinically meaningful difference (absolute difference of ORR in virally-infected vs uninfected=-1.4%, 95% CI: -13.5% to 10.6%). There was no relationship between viral etiology on features of the tumor immune microenvironment that are known to modulate responses to PD-1/PD-L1 inhibitors, and the tumor mutational burden was similar between virally-infected and uninfected HCC. RNA sequencing of tissue-resident T cell and B cell repertoires similarly showed no effect of viral status on their diversity. CyTOF analysis of peripheral blood specimens further demonstrated similar expression of immune-related markers in response to PD-1 inhibitor therapy in virally-infected and uninfected HCC. CONCLUSION:There is no significant effect of viral etiology on the tumor immune microenvironment in HCC, and viral status should not be used as a criterion to select patients for PD-1/PD-L1 therapy. 10.1136/jitc-2019-000394
    Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer: A Meta-analysis and Individual Patient-Level Analysis. Yu Yunfang,Zeng Dongqiang,Ou Qiyun,Liu Shengbo,Li Anlin,Chen Yongjian,Lin Dagui,Gao Quanlong,Zhou Haiyu,Liao Wangjun,Yao Herui JAMA network open Importance:The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non-small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition. Objectives:To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors. Data Sources:The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including tumor vaccine, cellular immunotherapy, immune checkpoint inhibitor, cytotoxic T-lymphocyte-associated protein 4, programmed death-ligand 1, programmed death receptor 1, and non-small cell lung carcinoma. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched. Study Selection:English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC. Data Extraction and Synthesis:Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used. I2 was used to assess the heterogeneity between trials; an I2 value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018. Main Outcomes and Measures:Primary outcomes were OS and PFS. Results:In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient-level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001). Conclusions and Relevance:Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies. 10.1001/jamanetworkopen.2019.6879
    Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumours: a guide to immunohistochemistry implementation and interpretation. Paver Elizabeth C,Cooper Wendy A,Colebatch Andrew J,Ferguson Peter M,Hill Sean K,Lum Trina,Shin Joo-Shik,O'Toole Sandra,Anderson Lyndal,Scolyer Richard A,Gupta Ruta Pathology Immunotherapy with checkpoint inhibitors is well established as an effective treatment for non-small cell lung cancer and melanoma. The list of approved indications for treatment with PD-1/PD-L1 checkpoint inhibitors is growing rapidly as clinical trials continue to show their efficacy in patients with a wide range of solid tumours. Clinical trials have used a variety of PD-L1 immunohistochemical assays to evaluate PD-L1 expression on tumour cells, immune cells or both as a potential biomarker to predict response to immunotherapy. Requests to pathologists for PD-L1 testing to guide choice of therapy are rapidly becoming commonplace. Thus, pathologists need to be aware of the different PD-L1 assays, methods of evaluation in different tumour types and the impact of the results on therapeutic decisions. This review discusses the key practical issues relating to the implementation of PD-L1 testing for solid tumours in a pathology laboratory, including evidence for PD-L1 testing, different assay types, the potential interchangeability of PD-L1 antibody clones and staining platforms, scoring criteria for PD-L1, validation, quality assurance, and pitfalls in PD-L1 assessment. This review also explores PD-L1 IHC in solid tumours including non-small cell lung carcinoma, head and neck carcinoma, triple negative breast carcinoma, melanoma, renal cell carcinoma, urothelial carcinoma, gastric and gastroesophageal carcinoma, colorectal carcinoma, hepatocellular carcinoma, and endometrial carcinoma. The review aims to provide pathologists with a practical guide to the implementation and interpretation of PD-L1 testing by immunohistochemistry. 10.1016/j.pathol.2020.10.007
    Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma. Park Dong-Jun,Sung Pil-Soo,Lee Gil-Won,Cho Sungwoo,Kim Sung-Min,Kang Byung-Yoon,Hur Wonhee,Yang Hyun,Lee Soon-Kyu,Lee Sung-Hak,Jung Eun-Sun,Seo Chang-Ho,Ahn Joseph,Choi Ho-Joong,You Young-Kyoung,Jang Jeong-Won,Bae Si-Hyun,Choi Jong-Young,Yoon Seung-Kew International journal of molecular sciences A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68 macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells ( < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8 T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4 and CD8 T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8 T cells in HCC. 10.3390/ijms22094710
    A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study. Sun Roger,Limkin Elaine Johanna,Vakalopoulou Maria,Dercle Laurent,Champiat Stéphane,Han Shan Rong,Verlingue Loïc,Brandao David,Lancia Andrea,Ammari Samy,Hollebecque Antoine,Scoazec Jean-Yves,Marabelle Aurélien,Massard Christophe,Soria Jean-Charles,Robert Charlotte,Paragios Nikos,Deutsch Eric,Ferté Charles The Lancet. Oncology BACKGROUND:Because responses of patients with cancer to immunotherapy can vary in success, innovative predictors of response to treatment are urgently needed to improve treatment outcomes. We aimed to develop and independently validate a radiomics-based biomarker of tumour-infiltrating CD8 cells in patients included in phase 1 trials of anti-programmed cell death protein (PD)-1 or anti-programmed cell death ligand 1 (PD-L1) monotherapy. We also aimed to evaluate the association between the biomarker, and tumour immune phenotype and clinical outcomes of these patients. METHODS:In this retrospective multicohort study, we used four independent cohorts of patients with advanced solid tumours to develop and validate a radiomic signature predictive of immunotherapy response by combining contrast-enhanced CT images and RNA-seq genomic data from tumour biopsies to assess CD8 cell tumour infiltration. To develop the radiomic signature of CD8 cells, we used the CT images and RNA sequencing data of 135 patients with advanced solid malignant tumours who had been enrolled into the MOSCATO trial between May 1, 2012, and March 31, 2016, in France (training set). The genomic data, which are based on the CD8B gene, were used to estimate the abundance of CD8 cells in the samples and data were then aligned with the images to generate the radiomic signatures. The concordance of the radiomic signature (primary endpoint) was validated in a Cancer Genome Atlas [TGCA] database dataset including 119 patients who had available baseline preoperative imaging data and corresponding transcriptomic data on June 30, 2017. From 84 input variables used for the machine-learning method (78 radiomic features, five location variables, and one technical variable), a radiomics-based predictor of the CD8 cell expression signature was built by use of machine learning (elastic-net regularised regression method). Two other independent cohorts of patients with advanced solid tumours were used to evaluate this predictor. The immune phenotype internal cohort (n=100), were randomly selected from the Gustave Roussy Cancer Campus database of patient medical records based on previously described, extreme tumour-immune phenotypes: immune-inflamed (with dense CD8 cell infiltration) or immune-desert (with low CD8 cell infiltration), irrespective of treatment delivered; these data were used to analyse the correlation of the immune phenotype with this biomarker. Finally, the immunotherapy-treated dataset (n=137) of patients recruited from Dec 1, 2011, to Jan 31, 2014, at the Gustave Roussy Cancer Campus, who had been treated with anti-PD-1 and anti-PD-L1 monotherapy in phase 1 trials, was used to assess the predictive value of this biomarker in terms of clinical outcome. FINDINGS:We developed a radiomic signature for CD8 cells that included eight variables, which was validated with the gene expression signature of CD8 cells in the TCGA dataset (area under the curve [AUC]=0·67; 95% CI 0·57-0·77; p=0·0019). In the cohort with assumed immune phenotypes, the signature was also able to discriminate inflamed tumours from immune-desert tumours (0·76; 0·66-0·86; p<0·0001). In patients treated with anti-PD-1 and PD-L1, a high baseline radiomic score (relative to the median) was associated with a higher proportion of patients who achieved an objective response at 3 months (vs those with progressive disease or stable disease; p=0·049) and a higher proportion of patients who had an objective response (vs those with progressive disease or stable disease; p=0·025) or stable disease (vs those with progressive disease; p=0·013) at 6 months. A high baseline radiomic score was also associated with improved overall survival in univariate (median overall survival 24·3 months in the high radiomic score group, 95% CI 18·63-42·1; vs 11·5 months in the low radiomic score group, 7·98-15·6; hazard ratio 0·58, 95% CI 0·39-0·87; p=0·0081) and multivariate analyses (0·52, 0·35-0·79; p=0·0022). INTERPRETATION:The radiomic signature of CD8 cells was validated in three independent cohorts. This imaging predictor provided a promising way to predict the immune phenotype of tumours and to infer clinical outcomes for patients with cancer who had been treated with anti-PD-1 and PD-L1. Our imaging biomarker could be useful in estimating CD8 cell count and predicting clinical outcomes of patients treated with immunotherapy, when validated by further prospective randomised trials. FUNDING:Fondation pour la Recherche Médicale, and SIRIC-SOCRATE 2.0, French Society of Radiation Oncology. 10.1016/S1470-2045(18)30413-3
    Analyses of PD-L1 and Inflammatory Gene Expression Association with Efficacy of Nivolumab ± Ipilimumab in Gastric Cancer/Gastroesophageal Junction Cancer. Lei Ming,Siemers Nathan O,Pandya Dimple,Chang Han,Sanchez Teresa,Harbison Christopher,Szabo Peter M,Janjigian Yelena,Ott Patrick A,Sharma Padmanee,Bendell Johanna,Evans Thomas R Jeffry,de Braud Filippo,Chau Ian,Boyd Zachary Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors. PATIENTS AND METHODS:In exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1-staining TCs + immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression. RESULTS:There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1-positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1-positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1-negative status. Similar results were observed in the NIVO 1 mg/kg + IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes (, and ), showed associations with response to NIVO ± IPI. CONCLUSIONS:This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.. 10.1158/1078-0432.CCR-20-2790
    Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. Kim Chang Gon,Kim Chan,Yoon Sang Eun,Kim Kyung Hwan,Choi Seong Jin,Kang Beodeul,Kim Hye Ryun,Park Su-Hyung,Shin Eui-Cheol,Kim Yeun-Yoon,Kim Dae Jung,Chung Hyun Cheol,Chon Hong Jae,Choi Hye Jin,Lim Ho Yeong Journal of hepatology BACKGROUND & AIMS:Programmed cell death-1 (PD-1) inhibitor treatment can cause hyperprogressive disease (HPD), but the incidence, outcome, and predictive factors of HPD are unknown in patients with hepatocellular carcinoma (HCC). Herein, we assessed the existence and factors predictive of HPD in patients with advanced HCC treated with nivolumab. METHODS:We enrolled 189 patients with advanced HCC treated with nivolumab. Occurrence of HPD was investigated using tumour growth dynamics based on tumour growth kinetics (TGK) and tumour growth rate (TGR) before and after treatment, or time to treatment failure. We additionally analysed patients treated with regorafenib (n = 95) or best supportive care (BSC)/placebo (n = 103) after progression on sorafenib to compare tumour growth dynamics. RESULTS:Flare-up of tumour growth was observed in a fraction of patients upon PD-1 blockade, indicating the occurrence of HPD. Based on distinct patterns of disease progression exclusively observed in the nivolumab-treated cohort, but not in the regorafenib- or BSC/placebo-treated cohorts, 4-fold increases in TGK and TGR ratios as well as a 40% increase in TGR were the cut-off values used to define HPD; 12.7% of the patients (24/189) treated with nivolumab met all these criteria. Patients with HPD had worse progression-free survival (hazard ratio [HR] 2.194; 95% CI 1.214-3.964) and overall survival (HR 2.238; 95% CI 1.233-4.062) compared to patients with progressive disease without HPD. More than 90% of patients with HPD missed the opportunity for subsequent treatment because of rapid clinical deterioration. An elevated neutrophil-to-lymphocyte ratio (>4.125) was associated with HPD and an inferior survival rate. CONCLUSIONS:HPD occurs in a fraction of patients with HCC who receive PD-1 inhibitor treatment. Analyses of the baseline immune profile and on-treatment tumour growth dynamics could enable optimal patient selection and earlier identification of HPD. LAY SUMMARY:Hyperprogressive disease is an unexpected response pattern observed in patients treated with an immune checkpoint inhibitor. This study revealed that hyperprogressive disease occurs in a fraction of patients with advanced hepatocellular carcinoma treated with an anti-PD-1 antibody, providing evidence to encourage careful monitoring of patients to prevent clinical deterioration induced by PD-1 blockade. 10.1016/j.jhep.2020.08.010
    Clinical benefits of PD-1/PD-L1 inhibitors in advanced hepatocellular carcinoma: a systematic review and meta-analysis. Rao Quan,Li Min,Xu Wei,Pang Kai,Guo XiaoBo,Wang Dong,Liu Jun,Guo Wei,Zhang ZhongTao Hepatology international BACKGROUND:Significant improvement of objective response rate and overall survival period has been achieved in several types of solid tumors by treatment with PD-1/PD-L1 inhibitors, which shed some light on hepatocellular carcinoma (HCC). Currently, a number of clinical trials concerning the application of checkpoint inhibitors in HCC are ongoing, some of which have shown favorable expectations. Hereby, we conducted a meta-analysis of existing studies to reveal the efficacy and safety of checkpoint inhibitors in advanced HCC. METHODS:Medline, Embase, Cochrane Library, and Web of Science were searched from inception to January 31, 2020. The clinical trials reporting the efficacy of PD-1/PD-L1 inhibitors in advanced HCC patients were eligible. Overall results of complete response (CR), partial response (PR), stable disease (SD), progression of disease (PD), objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS) and rate of adverse events (AE) with their 95% confidence intervals (95%CI) were calculated as the primary focus of the meta-analysis. Subgroup analyses were conducted primarily according to the categories of PD-1 inhibitor or PD-L1 inhibitor and combination therapy or monotherapy. In addition, pooled results of PD-1/PD-L1 monoclonal antibodies (mAb) combining with anti-VEGF agents were calculated separately. RESULTS:A total of 20 studies with 1232 patients were included. The overall CR, PR and SD rate were 0.01 (95% CI 0.01-0.03), 0.17 (95% CI 0.14-0.22) and 0.39 (95% CI 0.34-0.43), respectively. The overall ORR and DCR were 0.20 (95% CI 0.16-0.24) and 0.60 (95% CI 0.54-0.67), respectively. The overall PFS and OS were 3.58 months (95% CI 2.65-4.50) and 12.24 months (95% CI 10.48-14.00), respectively. For patients treated with PD-1/PD-L1 mAb combing with anti-VEGF agent, ORR was 29% (95% CI 0.15-0.43) and DCR was 77% (95% CI 0.70-0.84). For all included studies, the overall rate of AE was 0.63 (95% CI 0.45-0.78) and serious adverse events (SAE) was 0.11 (95% CI 0.06-0.22). CONCLUSIONS:PD-1/PD-L1 inhibitors showed favorable outcomes concerning response rates and survival periods in advanced HCC. Updated results from high-quality clinical trials are expected to validate these findings. 10.1007/s12072-020-10064-8
    Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: current knowledge and future research directions. Hilmi Marc,Neuzillet Cindy,Calderaro Julien,Lafdil Fouad,Pawlotsky Jean-Michel,Rousseau Benoit Journal for immunotherapy of cancer Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies. 10.1186/s40425-019-0824-5
    Optimizing Survival and the Changing Landscape of Targeted Therapy for Intermediate and Advanced Hepatocellular Carcinoma: A Systematic Review. Lim Howard,Ramjeesingh Ravi,Liu Dave,Tam Vincent C,Knox Jennifer J,Card Paul B,Meyers Brandon M Journal of the National Cancer Institute BACKGROUND:Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice. METHODS:Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA). RESULTS:Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection. CONCLUSIONS:Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation. 10.1093/jnci/djaa119
    Immune Checkpoint Inhibitors as Monotherapy or Within a Combinatorial Strategy in Advanced Hepatocellular Carcinoma. Guardascione Michela,Toffoli Giuseppe International journal of molecular sciences In advanced-stage hepatocellular carcinoma (HCC), systemic treatment represents the standard therapy. Target therapy has marked a new era based on a greater knowledge of molecular disease signaling. Nonetheless, survival outcomes and long-term response remain unsatisfactory, mostly because of the onset of primary or acquired resistance. More recently, results from clinical trials with immune targeting agents, such as the immune checkpoint inhibitors (ICIs), have shown a promising role for these drugs in the treatment of advanced HCC. In the context of an intrinsic tolerogenic liver environment, since HCC-induced immune tolerance, it is supported by multiple immunosuppressive mechanisms and several clinical trials are now underway to evaluate ICI-based combinations, including their associations with antiangiogenic agents or multikinase kinase inhibitors and multiple ICIs combinations. In this review, we will first discuss the basic principles of hepatic immunogenic tolerance and the evasive mechanism of antitumor immunity in HCC; furthermore we will elucidate the consistent biological rationale for immunotherapy in HCC even in the presence of an intrinsic tolerogenic environment. Subsequently, we will critically report and discuss current literature on ICIs in the treatment of advanced HCC, including a focus on the currently explored combinatorial strategies and their rationales. Finally, we will consider both challenges and future directions in this field. 10.3390/ijms21176302
    Comparative safety and efficacy of molecular-targeted drugs, immune checkpoint inhibitors, hepatic arterial infusion chemotherapy and their combinations in advanced hepatocellular carcinoma: findings from advances in landmark trials. Pan Yangxun,Wang Ruojing,Hu Dandan,Xie Wa,Fu Yizhen,Hou Jiajie,Xu Li,Zhang Yaojun,Chen Minshan,Zhou Zhongguo Frontiers in bioscience (Landmark edition) : Several recent phase 3 trials have reported manageable safety profiles and promising antitumor activities of molecular-targeted drugs (MTDs; sorafenib, lenvatinib), immune checkpoint inhibitors (ICIs; nivolumab, pembrolizumab, atezolizumab), hepatic arterial infusion chemotherapy (HAIC) and their combinations in advanced hepatocellular carcinoma (AHCC); however, head-to-head comparisons among these regimens are lacking. : We aimed to comprehensively review and compare the efficacy and safety of different MTDs, ICIs, HAIC and their combinations in AHCC. Adverse events (AEs), disease control rates (DCRs), objective response rates (ORRs), overall survival (OS) and progression-free survival (PFS) were assessed. : The pooled incidence rates of grade 1-5/3-5 AEs were 98.0%/48.6%, 98.3%/57.4%, 91.4%/22.0%, 96.4%/54.6%, 98.2%/61.1%, 86.3%/34.1%, 88.9%/9.4%, and 95.2%/53.2% for sorafenib, lenvatinib, nivolumab, pembrolizumab, atezolizumab plus bevacizumab, HAIC-cisplatin plus sorafenib, HAIC-oxaliplatin, and HAIC-oxaliplatin plus sorafenib, respectively, which suggested that nivolumab exhibited optimal safety regarding grade 1-5 AEs, whereas HAIC-oxaliplatin monotherapy ranked lowest regarding grade 3-5 AEs. According to RECIST1.1, lenvatinib (72.8%), atezolizumab plus bevacizumab (73.6%), HAIC-oxaliplatin (78.8%) and HAIC-oxaliplatin plus sorafenib (75.2%) showed higher DCRs than sorafenib (57.3%), nivolumab (33.9%), and pembrolizumab (62.3%), whereas only HAIC-oxaliplatin-based treatments demonstrated a higher ORR than the others. Pooled OS and PFS analysis favored the combination regimens other than sorafenib along. : Here, we present preliminary evidence for the comparative safety and efficacy of existing MTDs, ICIs, HAIC and their combinations in AHCC, which indicated that HAIC-oxaliplatin monotherapy has acceptable toxicity and efficacy and could be the cornerstone for future combination of systemic treatments in AHCC. Our findings might provide insight into the future design of multidisciplinary treatments in AHCC. 10.52586/4994
    Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma. Liu Ziyu,Lin Yan,Zhang Jinyan,Zhang Yumei,Li Yongqiang,Liu Zhihui,Li Qian,Luo Ming,Liang Rong,Ye Jiazhou Journal of experimental & clinical cancer research : CR Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC. 10.1186/s13046-019-1412-8
    Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma. Xing Rui,Gao Jinping,Cui Qi,Wang Qian Frontiers in immunology Hepatocellular carcinoma (HCC), one of the most fatal malignancies in the world, is usually diagnosed in advanced stages due to late symptom manifestation with very limited therapeutic options, which leads to ineffective intervention and dismal prognosis. For a decade, tyrosine kinase inhibitors (TKIs) have offered an overall survival (OS) benefit when used in a first-line (sorafenib and lenvatinib) and second-line setting (regorafenib and cabozantinib) in advanced HCC, while long-term response remains unsatisfactory due to the onset of primary or acquired resistance. Recently, immunotherapy has emerged as a promising therapy in the treatment of several solid tumors, such as melanoma and non-small cell lung cancer. Moreover, as the occurrence of HCC is associated with immune tolerance and immunosurveillance escape, there is a potent rationale for employing immunotherapy in HCC. However, immunotherapy monotherapy, mainly including immune checkpoint inhibitors (ICIs) that target checkpoints programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and the cytotoxic T lymphocyte antigen-4 (CTLA-4), has a relatively low response rate. Thus, the multi-ICIs or the combination of immunotherapy with other therapies, like antiangiogenic drugs and locoregional therapies, has become a novel strategy to treat HCC. Combining different ICIs may have a synergistical effect attributed to the complementary effects of the two immune checkpoint pathways (CTLA-4 and PD-1/PD-L1 pathways). The incorporation of antiangiogenic drugs in ICIs can enhance antitumor immune responses synergistically regulating the vasculature and the immune microenvironment of tumor. In addition, locoregional treatments can improve antitumor immunity by releasing the neoplasm antigens from killed tumor cells; in turn, this antitumor immune response can be intensified by immunotherapy. Therefore, the combination of locoregional treatments and immunotherapy may achieve greater efficacy through further synergistic effects for advanced HCC. This review aims to summarize the currently reported results and ongoing trials of the ICIs-based combination therapies for HCC to explore the rational combination strategies and further improve the survival of patients with HCC. 10.3389/fimmu.2021.783236
    Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. Sangro Bruno,Melero Ignacio,Wadhawan Samir,Finn Richard S,Abou-Alfa Ghassan K,Cheng Ann-Lii,Yau Thomas,Furuse Junji,Park Joong-Won,Boyd Zachary,Tang Hao Tracy,Shen Yun,Tschaika Marina,Neely Jaclyn,El-Khoueiry Anthony Journal of hepatology BACKGROUND & AIMS:Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. METHODS:Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). RESULTS:Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). CONCLUSIONS:PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. LAY SUMMARY:Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. NCT NUMBER:NCT01658878. 10.1016/j.jhep.2020.07.026
    mRECIST response combined with sorafenib-related adverse events is superior to either criterion alone in predicting survival in HCC patients treated with TACE plus sorafenib. Wang Wenjun,Bai Wei,Wang Enxin,Zhao Yan,Liu Lei,Yang Man,Cai Hongwei,Xia Dongdong,Zhang Lei,Niu Jing,Yin Zhanxin,Zhang Zhuoli,Fan Daiming,Xia Jielai,Han Guohong International journal of cancer The mRECIST and dermatologic adverse events (AEs) can be used to assess the patient response to transarterial chemoembolization (TACE) and/or sorafenib for hepatocellular carcinoma (HCC). Here, we aimed to combine the two criteria to stratify the prognosis in patients with unresectable HCC receiving TACE plus sorafenib (TACE-S). In total, 176 consecutive HCC patients treated with TACE-S were enrolled. CT scans and laboratory tests were conducted pretreatment (at baseline, 5-7 days before the TACE-S) and post-treatment (at 1, 2 and 3 months). The radiological response was assessed according to mRECIST. Sorafenib-related AEs were recorded every 2 weeks after oral administration, and patients with dermatologic AEs of Grade 2 or more were defined as dermatologic responders. The earliest time at which mRECIST and dermatologic responses correlated with survival was 2 months after therapy. The mRECIST-dermatologic AE combination assessment stratified patients into three different prognoses; responders on both assessments exhibited the longest median overall survival (OS), followed by responders on one assessment and non-responders on both assessments (30.5, 17.4 and 8.3 months, respectively; p < 0.001). Achieving the highest C-index, the mRECIST-dermatologic AE combination showed better performance in predicting survival than either mRECIST or dermatologic AEs alone. Furthermore, the mRECIST-dermatologic AE combination remained a significant predictor of OS, even when the patients were stratified according to the BCLC stage, ECOG score or alpha-fetoprotein (AFP) value. This study showed that the combination of mRECIST response and dermatologic AEs is superior to either criterion used alone for predicting the survival of HCC patients treated with TACE-S. 10.1002/ijc.30451
    Early Changes in DCE-MRI Biomarkers May Predict Survival Outcomes in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure: Two Prospective Phase II Trials. Chen Bang-Bin,Lin Zhong-Zhe,Shao Yu-Yun,Hsu Chiun,Hsu Chih-Hung,Cheng Ann-Lii,Liang Po-Chin,Shih Tiffany Ting-Fang Cancers In this paper, our main objective was to predict survival outcomes using DCE-MRI biomarkers in patients with advanced hepatocellular carcinoma (HCC) after progression from 1st-line sorafenib treatment in two prospective phase II trials. This study included 74 participants (men/women = 64/10, mean age 60 ± 11.8 years) with advanced HCC who received 2nd-line targeted therapy ( = 41 with lenalidomide in one clinical trial; = 33 with axitinib in another clinical trial) after sorafenib failure from two prospective phase II studies. Among them, all patients underwent DCE-MRI at baseline, and on days 3 and 14 of treatment. The relative changes (Δ) in the DCE-MRI parameters, including ΔPeak, ΔAUC, and ΔK, were derived from the largest hepatic tumor. The treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The Cox model was used to investigate the associations of the clinical variables and DCE-MRI biomarkers with progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was 10.8% (8/74) and the disease control rate (DCR) was 58.1% (43/74). The median PFS and OS values were 1.9 and 7.8 months, respectively. On day 3 (D3), participants with high reductions in ΔPeak_D3 (hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.17-0.93, = 0.017) or ΔAUC_D3 (HR 0.51, 95% CI 0.25-1.04, = 0.043) were associated with better PFS. On day 14, participants with high reductions in ΔPeak_D14 (HR 0.51, 95% CI 0.26-1.01, = 0.032), ΔAUC_D14 (HR 0.54, 95% CI 0.33-0.9, = 0.009), or ΔK_D14 (HR 0.26, 95% CI 0.12-0.56, < 0.001) had a higher PFS than those with lower reduction values. In addition, high reductions in ΔAUC_D14 (HR 0.53, 95% CI 0.32-0.9, = 0.016) or ΔK_D14 (HR 0.47, 95% CI 0.23-0.98, = 0.038) were associated with a better OS. Among the clinical variables, ORR was associated with both PFS ( = 0.001) and OS ( = 0.005). DCR was associated with PFS ( = 0.002), but not OS ( = 0.089). Cox multivariable analysis revealed that ΔK_D14 ( = 0.002) remained an independent predictor of PFS after controlling for ORR and DCR. An early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict favorable survival outcomes in participants with HCC receiving 2nd-line targeted therapy after sorafenib failure. 10.3390/cancers13194962
    Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial. Qin Shukui,Bi Feng,Gu Shanzhi,Bai Yuxian,Chen Zhendong,Wang Zishu,Ying Jieer,Lu Yinying,Meng Zhiqiang,Pan Hongming,Yang Ping,Zhang Helong,Chen Xi,Xu Aibing,Cui Chengxu,Zhu Bo,Wu Jian,Xin Xiaoli,Wang Jufeng,Shan Jinlu,Chen Junhui,Zheng Zhendong,Xu Li,Wen Xiaoyu,You Zhenyu,Ren Zhenggang,Liu Xiufeng,Qiu Meng,Wu Liqing,Chen Feng Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS:This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS:Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 3.6 months ( .0570). The objective response rate was 4.6% 2.7% ( = .2448), and the disease control rate was 30.8% 28.7% (FAS; = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] 165 [50%]; .0018). CONCLUSION:Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients. 10.1200/JCO.21.00163
    Efficacy and Safety of Camrelizumab Monotherapy and Combination Therapy for Cancers: A Systematic Review and Meta-Analysis. Frontiers in oncology OBJECTIVE:This meta-analysis compared the safety and efficacy of camrelizumab monotherapy and combination therapy, aiming to provide a reference for the clinical combined use of camrelizumab in the treatment of cancers and also provide a reference for the development of subsequent indications of camrelizumab. METHODS:Meta-analysis was used to analyze the four eligible literatures. Primary endpoints of effectiveness index were objective response rate (ORR), progression-free survival (PFS), control rate (CR). Primary endpoint of safety index was rating of severity of adverse drug reactions (grades 1-5). RESULTS:The ORR, PFS, and CR values of combined treatment with camrelizumab was better than alone treatment, camrelizumab alone was better than chemotherapy (RR = 0.45; 95% CI, 0.30-0.67; P < 0.001; RR = 1.63; 95% CI, 1.25-2.13; P < 0.001; RR = 0.73; 95% CI, 0.52-1.02; P<0.001). When grade > 2, the incidence rate of combined treatment and chemotherapy are higher than monotherapy (RR = 0.66; 95% CI, 0.51-0.86; P<0.001). In any grade, the safety of camrelizumab combination therapy was better than that of monotherapy, the safety of chemotherapy was better than camrelizumab plus chemotherapy. CONCLUSION:In terms of effectiveness, the combination of camrelizumab is better than monotherapy, and monotherapy is better than chemotherapy. In terms of safety, when the grade > 2, single use is better than combination therapy and chemotherapy. In any grade of adverse event, the safety of combined use of camrelizumab is better than that of single use, and the safety of chemotherapy is better than the combined use of camrelizumab plus chemotherapy. 10.3389/fonc.2021.695512
    Transarterial chemoembolization plus lenvatinib versus transarterial chemoembolization plus sorafenib as first-line treatment for hepatocellular carcinoma with portal vein tumor thrombus: A prospective randomized study. Ding Xiaoyan,Sun Wei,Li Wei,Shen Yanjun,Guo Xiaodi,Teng Ying,Liu Xiaomin,Zheng Linlin,Li Wendong,Chen Jinglong Cancer BACKGROUND:The efficacy and safety of transarterial chemoembolization (TACE) plus lenvatinib in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) have not been evaluated. METHODS:In this open-label, single-center, randomized trial (ClinicalTrials.gov identifier: NCT04127396), participants with previously untreated HCC and type I-IV PVTT were randomized 1:1 to receive TACE plus lenvatinib (arm L; orally once daily, 12 mg for body weight ≥60 kg or 8 mg for body weight <60 kg) or TACE plus sorafenib (arm S; 400 mg orally twice daily in 28-day cycles). The primary end point was time-to-progression (TTP; time from randomization to disease progression) and secondary end points included objective response rate and toxicity. Prognostic factors were evaluated using a multivariable Cox proportional hazards model. RESULTS:Between December 30, 2018 and May 31, 2020, 64 patients were randomized (arm L, n = 32; arm S, n = 32); most patients had type I/II PVTT (71.9%), and the median target tumor diameter was 9.8 cm (range, 3.8-21.8). After a median follow-up of 16.1 months, patients in arm L had a higher median TTP (4.7 vs 3.1 months; hazard ratio [HR], 0.55; 95% CI, 0.32-0.95; P = .029) and objective response rate (53.1% vs 25.0%, P = .039) versus arm S. Multivariable analysis showed that TACE plus lenvatinib was significantly associated with higher TTP versus TACE plus sorafenib (HR, 0.50; 95% CI, 0.28-0.90; P = .021). Comparable safety profiles were observed in arms L and S. CONCLUSIONS:TACE plus lenvatinib was safe, well tolerated, and had favorable efficacy versus TACE plus sorafenib in patients with advanced HCC with PVTT and large tumor burden. LAY SUMMARY:Hepatocellular carcinoma with portal vein tumor thrombus has a poor prognosis. In addition, most phase 3 trials of drugs for hepatocellular carcinoma exclude patients with major portal vein invasion, and treatment options for these patients are limited. Transarterial chemoembolization has shown promising efficacy in these patients, especially in combination with systemic treatment or radiotherapy. However, transarterial chemoembolization plus lenvatinib has not been investigated in this setting. This open-label, single-center, randomized trial showed that transarterial chemoembolization plus lenvatinib is safe, well tolerated, and has favorable efficacy versus transarterial chemoembolization plus sorafenib for the treatment of hepatocellular carcinoma with portal vein tumor thrombus. 10.1002/cncr.33677
    Microvascular Invasion as a Predictor of Response to Treatment with Sorafenib and Transarterial Chemoembolization for Recurrent Intermediate-Stage Hepatocellular Carcinoma. Peng Zhenwei,Chen Shuling,Xiao Han,Wang Yu,Li Jiaping,Mei Jie,Chen Zebin,Zhou Qian,Feng Shiting,Chen Minshan,Qian Guojun,Peng Sui,Kuang Ming Radiology Background The evidence of combining sorafenib with transarterial chemoembolization (TACE) for intermediate-stage recurrent hepatocellular carcinoma (HCC) is limited. Patient responses to this treatment varied because of the heterogeneous nature of intermediate-stage recurrent HCC, making it important to identify patients who are most likely to benefit from this combination therapy. Purpose To compare sorafenib administered in combination with TACE versus TACE alone in the treatment of recurrent intermediate-stage HCC after initial hepatectomy and to determine the relationship of microvascular invasion (MVI) to survival. Materials and Methods In this retrospective multicenter study, 3652 consecutive patients were found to have intrahepatic recurrences after initial hepatectomy of primary HCC from January 2010 to December 2016. Of these, 260 patients with intermediate-stage recurrent HCC underwent combination treatment with sorafenib and TACE or TACE alone. Overall survival (OS) and progression-free survival (PFS) were compared between these two treatments according to MVI status by using log-rank tests. Results A total of 128 patients were administered combination therapy (mean age, 55 years ± 7.6 [standard deviation]; 107 men) and 132 patients were administered TACE alone (mean age, 56 years ± 8.3; 110 men). The 5-year OS and PFS were higher in the combination group than in the TACE group (OS: 38.9% vs 20.5%, respectively, = .01; PFS, 37.5% vs 18.7%, respectively, = .003). For patients with MVI-positive lesions, the median OS and PFS after combination treatment ( = 55) were longer than those after TACE alone ( = 72; OS: 17.2 months vs 12.1 months, respectively, = .02; PFS: 17.0 months vs 11.0 months, respectively, = .02). Multivariable analysis showed that tumor number, MVI status, and treatment allocation were significant predictors of OS and PFS, whereas tumor size was a prognostic factor for PFS. Conclusion Patients with recurrent intermediate-stage hepatocellular carcinoma and lesions positive for microvascular invasion (MVI) had longer survival times by using a combined treatment of sorafenib with transarterial chemoembolization (TACE) compared with TACE alone; patients with MVI-negative lesions did not show survival benefit from combined therapy. © RSNA, 2019 See also the editorial by Malloy in this issue. 10.1148/radiol.2019181818
    Transarterial Chemoembolization (TACE) Plus Sorafenib Compared to TACE Alone in Transplant Recipients with Hepatocellular Carcinoma: An Institution Experience. Abdelrahim Maen,Victor David,Esmail Abdullah,Kodali Sudha,Graviss Edward A,Nguyen Duc T,Moore Linda W,Saharia Ashish,McMillan Robert,Fong Joy N,Uosef Ahmed,Elshawwaf Mahmoud,Heyne Kirk,Ghobrial Rafik M Cancers BACKGROUND:Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. Transarterial chemoembolization has shown survival benefits in patients with early to intermediate-stage HCC, becoming the standard of care and recommended treatment modality by most clinical practice guidelines. The most recent trials of the TACE plus sorafenib combined therapy in patients with unresectable HCC have yielded inconsistent outcomes. The purpose of this study was to compare the outcomes of HCC patients treated with the TACE sorafenib combination as opposed to TACE monotherapy. METHODS:This retrospective study included all patients with unresectable HCC who underwent liver transplantation and were treated by either TACE alone or TACE plus sorafenib between July 2008-December 2019. Demographic and clinical data as well as HCC recurrence post-liver transplant (LT) were reported as frequencies and proportions for categorical variables and as the median and interquartile range (IQR) or mean. Chi-square or Fisher's exact tests were performed for categorical variables and the Kruskal-Wallis test or unpaired test was performed for continuous variables. Kaplan-Meier curves present overall patient survival and HCC-free survival. RESULTS:A total of 128 patients received LT, with a median (IQR) age of 61.4 (57.0, 66.3) years; most were males (77%). Within the TACE-only group, 79 (77%) patients met the Milan criteria and 24 (23%) were beyond the Milan criteria, while the TACE plus sorafenib group had a higher proportion of patients beyond the Milan criteria: 16 (64%) vs. 9 (36%); = 0.01. The five-year disease-free survival (DFS) between the treatment groups approached significance, with 100% DFS in the TACE plus sorafenib group vs. 67.2% in the TACE-alone group, = 0.07. Five-year patient survival was 77.8% in the TACE plus sorafenib group compared to 61.5% in the TACE-alone group ( = 0.51). However, in patients who met the beyond Milan criteria, those who received TACE alone had a lower average amount of (percent) tumor necrosis on explant pathology (43.8% ± 32%) compared to patients who received TACE plus sorafenib (69.6% ± 32.8%, = 0.03). CONCLUSION:This study identified that using TACE plus sorafenib is generally well-tolerated and demonstrated improved overall survival compared to TACE only in transplant recipients with unresectable HCC. A multi-center and prospective randomized controlled trial is needed to substantiate these findings. 10.3390/cancers14030650
    The Efficacy and Safety of Apatinib Plus Camrelizumab in Patients With Previously Treated Advanced Biliary Tract Cancer: A Prospective Clinical Study. Wang Dongxu,Yang Xu,Long Junyu,Lin Jianzhen,Mao Jinzhu,Xie Fucun,Wang Yunchao,Wang Yanyu,Xun Ziyu,Bai Yi,Yang Xiaobo,Guan Mei,Pan Jie,Seery Samuel,Sang Xinting,Zhao Haitao Frontiers in oncology Background:PD-1/L1 inhibitor-based immunotherapy is currently under investigation in biliary tract cancer (BTC). Apatinib combined with camrelizumab has achieved promising results in various tumor types. The aim of this study was to assess the safety and efficacy of apatinib plus camrelizumab for advanced biliary tract cancer patients who have received previously treatments. Methods:This prospective, non-randomized, open-label trial was conducted at Peking Union Medical College Hospital (PUMCH). All included patients received apatinib orally at 250 mg per a day and camrelizumab intravenously at 200 mg every three weeks until disease progression or intolerable toxicity occurred. Efficacy was evaluated based on the Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1). Adverse events (AEs) were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Results:A total of 22 patients were consecutively enrolled from 1st December, 2018 until 1st August, 2020. Among 21 patients for whom we could conduct efficacy evaluations, no patients achieved a complete response (CR), 4 patients (19%) achieved partial response (PR), and 11 patients had stable disease with a disease control rate of 71.4%. The median overall survival was 13.1 months (95% CI, 8.1-18.2), and the median progression-free survival was 4.4 months (95% CI, 2.4-6.3). All patients experienced treatment related AEs, and grade 3 or 4 AEs occurred in 14 (63.6%) of 22 patients. No treatment related deaths were observed. Conclusions:This is the first report focusing on the efficacy and safety of camrelizumab plus apatinib in pretreated biliary tract cancer patients. The finding suggests this regimen has favorable therapeutic effects with relatively manageable toxicity. Further trials with a control arm are required to investigate. Clinical Trial Registration:identifier NCT04642664. 10.3389/fonc.2021.646979
    Chemoembolization Plus Radiotherapy Versus Chemoembolization Plus Sorafenib for the Treatment of Hepatocellular Carcinoma Invading the Portal Vein: A Propensity Score Matching Analysis. Chu Hee Ho,Kim Jin Hyoung,Shim Ju Hyun,Yoon Sang Min,Kim Pyeong Hwa,Alrashidi Ibrahim Cancers A combination of transarterial chemoembolization (TACE) plus sorafenib or radiotherapy (RT) has demonstrated efficacy in patients with advanced hepatocellular carcinoma (HCC). Here, the two combined treatment approaches were compared in patients with HCC and portal vein tumor thrombus (PVTT). Data from 307 patients treated with TACE plus RT (n = 203) or TACE plus sorafenib (n = 104) as first-line treatment for HCC with PVTT were retrospectively evaluated. Using the propensity model to correct selection bias, 87 patients were included from each treatment group. During follow up (median, 12 months) in the entire study population, the median progression-free survival (PFS) and overall survival (OS) were significantly longer in the TACE plus RT group than in the TACE plus sorafenib group (6.5 vs. 4.3 months, respectively; p = 0.017 and 16.4 vs. 12 months, respectively; p = 0.007). Following propensity score matching, the median PFS and OS in the two groups showed no statistically significant difference. Multivariable analysis found no significant association between PFS or OS and the treatment type. In conclusion, this retrospective study of data from patients with advanced HCC with PVTT shows that PFS and OS did not differ significantly in patients treated with TACE plus RT and TACE plus sorafenib. 10.3390/cancers12051116
    Efficacy and Safety of SBRT Combined With Camrelizumab and Apatinib in HCC Patients With PVTT: Study Protocol of a Randomized Controlled Trial. Frontiers in oncology BACKGROUND:Hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) has poor prognosis. Sorafenib/lenvatinib is recommended as the first-line therapy in these patients currently, with unsatisfactory response and survival benefit reported. Radiotherapy (RT) is increasingly utilized in advanced HCC and is considered an alternative option for HCC patients with PVTT. Combined treatment of RT and locoregional treatments such as transarterial chemoembolization shows promising results. However, the efficacy and safety for combined treatment of RT and systemic therapy have not been reported and thus warrant further studies. This prospective clinic trial aims at evaluating the efficacy and safety of stereotactic body RT (SBRT) combined with camrelizumab and apatinib in HCC patients with PVTT. METHODS:This multicenter, open-label, randomized controlled trial will enroll 264 HCC patients with PVTT who have not received systemic therapy previously. Stratification of patients will be based on the presence or absence of extrahepatic metastasis and level of AFP (AFP ≥ 400 or <400 ng/mL) and randomly assigned 1:1 to study and control groups. Patients in study group will receive SBRT (95% PTV 36-40 Gy/6-8 Gy), camrelizumab (200 mg every 3 weeks), and apatinib (250 mg every day), and patients in control group will receive camrelizumab (200 mg every 2 weeks) and apatinib (250 mg every day). Patients will be followed up for 1.5 to 3.5 years since the start of therapy. We will use overall survival as the primary endpoint and progression-free survival, objective response rate, disease control rate, adverse events, and quality of life as the secondary endpoints. DISCUSSION:This study will be the first randomized controlled trial to assess the efficacy and safety of SBRT combined with camrelizumab and apatinib for HCC patients with PVTT. The results may help establish a new standard first-line therapy for these patients. TRIAL REGISTRATION:Chinese Clinical Trial Registration No. ChiCTR1900027102. DATE OF REGISTRATION:October 31, 2019. 10.3389/fonc.2020.01589
    Safety and Efficacy of Transcatheter Arterial Chemoembolization Plus Radiotherapy Combined With Sorafenib in Hepatocellular Carcinoma Showing Macrovascular Invasion. Zhao Yuting,Zhu Xianggao,Wang Hongzhi,Dong Dezuo,Gao Song,Zhu Xu,Wang Weihu Frontiers in oncology The safety and efficacy of transcatheter arterial chemoembolization (TACE) plus intensity-modulated radiotherapy (IMRT) combined with sorafenib in hepatocellular carcinoma (HCC) showing macrovascular invasion (MVI) remain controversial. The records of 63 patients with HCC showing MVI, who underwent IMRT plus TACE combined with (28 participants; Group A) or without (35 participants; Group B) sorafenib from 2015 to 2018, were retrospectively reviewed to assess the progression-free survival (PFS), overall survival (OS), and treatment-associated toxicity. The median PFS was longer in Group A (13.6 months) than in Group B (9.2 months), and still significant after propensity score matching (PSM). However, the median OS was similar in the two groups (19.0 vs. 15.2 months, = 0.094 before PSM; = 0.204 after PSM). The grade 3 hematologic and hepatic toxicity was present in 10 (15.9%) and 7 (11.1%) patients, respectively. The incidence of skin reaction, hand-foot syndrome, and diarrhea, all grade 1-2 adverse events, was significantly higher in Group A than in Group B. No patient experienced grade 4 or 5 toxicity, and radiation-induced liver disease was also not observed. TACE plus IMRT combined with sorafenib showed a good safety profile and clinical benefit in patients with HCC having MVI. 10.3389/fonc.2019.01065
    Sorafenib for advanced hepatocellular carcinoma provides better prognosis after liver transplantation than without liver transplantation. Lee Soon Kyu,Jang Jeong Won,Nam Heechul,Sung Pil Soo,Kim Hee Yeon,Kwon Jung Hyun,Lee Sung Won,Song Do Seon,Kim Chang Wook,Song Myeong Jun,Choi Ho Joong,You Young Kyoung,Bae Si Hyun,Choi Jong Young,Yoon Seung Kew Hepatology international BACKGROUND:Although sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), the efficacy of sorafenib in patients with recurrent HCCs after liver transplantation (LT) has not been compared with that in patients without LT (non-LT). METHODS:Between 2008 and 2019, a total of 832 consecutive HCC patients treated with sorafenib (790 in the non-LT group and 42 in the LT group) were enrolled. The primary outcome was overall survival (OS). Secondary outcomes were time-to-progression (TTP), objective response rate (ORR) and disease control rate (DCR). Treatment outcomes were assessed by multiple subgroup analyses and propensity-score matching (PSM). RESULTS:The median follow-up duration was 152.5 days. The LT group was younger and had smaller intrahepatic HCC than the non-LT group. The LT group showed significantly better OS (16.8 vs. 7.1 months, p < 0.001), TTP, ORR and DCR than the non-LT group. The superior efficacy of sorafenib in the LT group was corroborated in multiple subgroup analyses stratified by metastasis, effective sorafenib maintenance dose, or Child-Turcotte-Pugh class A. LT was identified as an independent factor for favorable OS. Intrahepatic HCC was the strongest tumor-related factor for both OS and TTP and was significantly associated with tumor response and hepatic function. Finally, subanalyses including only patients with small intrahepatic HCC or PSM modeling showed no difference in sorafenib efficacy between the LT and the non-LT groups. CONCLUSION:Sorafenib provides better outcomes in the LT setting than the non-LT setting. This benefit may be associated with the smaller intrahepatic HCC coupled with preserved hepatic function in LT recipients. 10.1007/s12072-020-10131-0
    Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study. Li Qi,Cao Mengran,Yuan Guosheng,Cheng Xiao,Zang Mengya,Chen Ming,Hu Xiaoyun,Huang Jing,Li Rong,Guo Yabing,Ruan Jian,Chen Jinzhang Frontiers in oncology Background:Combining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC). Aims:To explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC. Methods:This multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety. Results:By March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events. Conclusion:First-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC. 10.3389/fonc.2022.809709
    Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. Jouve Jean-Louis,Lecomte Thierry,Bouché Olivier,Barbier Emilie,Khemissa Akouz Faiza,Riachi Ghassan,Nguyen Khac Eric,Ollivier-Hourmand Isabelle,Debette-Gratien Maryline,Faroux Roger,Villing Anne-Laure,Vergniol Julien,Ramee Jean-François,Bronowicki Jean-Pierre,Seitz Jean-François,Legoux Jean-Louis,Denis Jacques,Manfredi Sylvain,Phelip Jean-Marc, Journal of hepatology BACKGROUND & AIMS:Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC. METHODS:The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (n = 323) were randomly assigned to sorafenib-pravastatin combination (n = 162) or sorafenib alone (n = 161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life. RESULTS:After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35 months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7 months vs. 10.5 months; hazard ratio = 1.00; p = 0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported. CONCLUSION:Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC. LAY SUMMARY:Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555. 10.1016/j.jhep.2019.04.021
    Transarterial chemoembolization combined with camrelizumab for recurrent hepatocellular carcinoma. Guo Yusheng,Ren Yanqiao,Chen Lei,Sun Tao,Zhang Weihua,Sun Bo,Zhu Licheng,Xiong Fu,Zheng Chuansheng BMC cancer PURPOSE:To evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with camrelizumab (hereafter, TACE-camrelizumab) in the treatment of patients with recurrent hepatocellular carcinoma (R-HCC) after curative resection. PATIENTS AND METHODS:R-HCC patients who underwent TACE plus camrelizumab or TACE-alone from January 2016 to August 2021 were retrospectively evaluated. Patients were assessed for tumor response, progression-free survival, survival rates and adverse events. RESULTS:Seventy-one patients were included in this study, including 20 patients in the TACE- camrelizumab group and 51 patients in the TACE-alone group. The objective response rate was 56.9% in the TACE-alone group and 40% in the TACE-camrelizumab group at 3 months (P = 0.201). The disease control rates were 84.3% in TACE-alone group and 80% in TACE-camrelizumab group at 3 months (P = 0.663). The progression-free survival (PFS) of the TACE-alone group was slightly longer than those of the TACE- camrelizumab group (9 months vs. 6 months). However, there were no statistically significant differences in the median PFS (P = 0.586). Similarly, there were no significant differences in the half-year and one-year survival rates (P = 0.304, P = 0.430). Multivariate analysis revealed that Neutrophil-to-lymphocyte ratio (NLR) was associated with PFS significantly. 75% patients developed at least one type of AEs related to camrelizumab in TACE-camrelizumab group, and no patients developed severe AEs. CONCLUSION:Comparing with TACE-Alone, the efficacy of TACE-camrelizumab for patients with R-HCC was similar. Meanwhile, the results of this study also indicated that TACE is still a better choice for patients with R-HCC. 10.1186/s12885-022-09325-6
    Safety and Efficacy of Camrelizumab Combined with Apatinib for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Multicenter Retrospective Study. Yuan Guosheng,Cheng Xiao,Li Qi,Zang Mengya,Huang Wei,Fan Wenzhe,Wu Tao,Ruan Jian,Dai Wencong,Yu Wenxuan,Chen Mian,Guo Yabing,Hu Xiaoyun,Chen Jinzhang OncoTargets and therapy Introduction:Previous trials demonstrated that anti-angiogenesis or anti-programmed death protein 1 (PD-1) monotherapy showed unsatisfied effect in advanced hepatocellular carcinoma (HCC). No study existed that focus on the effects of camrelizumab and apatinib ("C+A") combination therapy for HCC patients with the location and extent of portal vein tumor thrombus (PVTT) as the main variable being assessed. This study was to compare the efficacy and tolerability of "C+A" for HCC patients with PVTT. Methods:We retrospectively analyzed patients with advanced HCC and PVTT who underwent "C+A" therapy in a multicenter retrospective cohort from Jan 2019 to July 2020. Outcomes of patients who underwent "C+A" were analyzed by using the Kaplan-Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). Results:Sixty-three patients were finally included and the mean duration of follow-up was 12.6 ± 4.5 months. The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 44.0% and 75.0%, respectively. The median overall survival (OS), progression-free survival (PFS) and time to progression (TTP) were 14.8 months, 11.8 months and not yet reached (NR), respectively. Patients with type B (OS, 15.9 months; PFS, 14.0 months; TTP, NR) or type C (OS, 16.0 months; PFS, 14.9 months; NR) PVTT appear to have better survival benefits compared with type A (OS, 5.8 months; PFS, 5.0 months; TTP, 7.0 months). Along with AFP, the absence of main PVTT was an independent predictive factor for survival at uni- and multivariate analysis. Conclusion:Camrelizumab and apatinib yielded a promising outcome in patients with advanced HCC who developed a tumor thrombus in the first lower-order portal vein branches and was generally safe and had manageable side effects. 10.2147/OTT.S286169
    Advanced hepatocellular carcinoma treated by transcatheter arterial chemoembolization with drug-eluting beads plus lenvatinib versus sorafenib, a propensity score matching retrospective study. Xue Miao,Wu Yanqin,Zhu Bowen,Zou Xinhua,Fan Wenzhe,Li Jiaping American journal of cancer research Recently, a prospective randomized study suggested that transcatheter arterial chemoembolization (TACE) plus lenvatinib, as opposed to TACE plus sorafenib, was an effective and promising treatment for patients with advanced hepatocellular carcinoma (HCC) having portal vein thrombus (PVTT) and large tumor burden. However, no propensity score matching retrospective studies on TACE with drug-eluting beads (DEB-TACE) plus lenvatinib (DEB-TACE+LEN) versus DEB-TACE plus sorafenib (DEB-TACE+SOR) for advanced HCC has been reported to date. The medical records of consecutive patients with advanced HCC who underwent DEB-TACE+LEN or DEB-TACE+SOR between January 2017 and December 2020 were retrospectively reviewed. Mutation genes (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by whole-exome sequencing (WES). Adverse events (AEs), objective response rate (ORR), disease control rate (DCR), overall survival (OS) and time to progression (TTP) were compared between patients who underwent DEB-TACE+LEN and DEB-TACE+SOR. In total, 150 patients were enrolled in this study. The DEB-TACE+LEN group (n=50) showed significantly better ORR (64.0% vs. 33.3%; =0.008), OS (hazard ratio [HR]=0.63, 95% confidence interval (CI): 0.41-0.98; =0.043), and TTP (HR=0.65, 95% CI: 0.45-0.94; =0.023) than that in the DEB-TACE+SOR group (n=100). Subgroup analyses showed that in patients with portal vein tumor thrombus (PVTT), OS and TTP were significantly longer in the DEB-TACE+LEN group than in the DEB-TACE+SOR group (HR=0.59, 95% CI: 0.36-0.98; =0.043; HR=0.89, 95% CI: 0.35-2.29; =0.035). In patients with FGF21 amplification, OS was also significantly longer in the DEB-TACE+LEN group than that in the DEB-TACE+SOR group (HR=0.19, 95% CI: 0.06-0.66; =0.003). The patients in DEB-TACE+LEN group had a significantly lower incidence of hand-foot skin reaction (32.0% vs. 49.0%; =0.048), but a higher incidence of proteinuria (26.0% vs. 10.0%; =0.010) than that in the DEB-TACE+SOR group. In conclusion, DEB-TACE+LEN conferred better ORR, OS and TTP than did DEB-TACE+SOR in patients with advanced HCC, especially those with PVTT and FGF21 amplification, with acceptable AEs; thus making it a superior treatment modality for these patients.
    Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial. Journal for immunotherapy of cancer OBJECTIVE:This study aimed to assess the efficacy and safety of camrelizumab plus apatinib in patients with resectable hepatocellular carcinoma (HCC) as neoadjuvant therapy. METHODS:Initially, 20 patients with HCC were screened and 18 patients with resectable HCC were enrolled in this open-label, single-arm, phase II clinical trial. Patients received three cycles of neoadjuvant therapy including three doses of camrelizumab concurrent with apatinib for 21 days followed by surgery. Four to 8 weeks after surgery, patients received eight cycles of adjuvant therapy with camrelizumab in combination with apatinib. Major pathological reactions (MPR), complete pathological reactions (pCR), objective response rate (ORR), relapse-free survival (RFS), and adverse events (AE) were assessed. In addition, cancer tissue and plasma samples were collected before and after treatment, and genetic differences between responding and non-responding lesions were compared by tumor immune microenvironment (TIME) analysis, circulating tumor DNA (ctDNA) analysis and proteomics analysis. RESULTS:In 18 patients with HCC who completed neoadjuvant therapy, 3 (16.7%) and 6 (33.3%) patients with HCC reached ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and modified RECIST criteria, respectively. Of the 17 patients with HCC who received surgical resection, 3 (17.6%) patients with HCC reported MPR and 1 (5.9%) patient with HCC achieved pCR. The 1-year RFS rate of the enrolled patients was 53.85% (95% CI: 24.77% to 75.99%). Grade 3/4 AEs were reported in 3 (16.7%) of the 18 patients, with the most common AEs being rash (11.1%), hypertension (5.6%), drug-induced liver damage (5.6%), and neutropenia (5.6%) in the preoperative phase. The 289 NanoString panel RNA sequencing showed that TIME cell infiltration especially dendritic cells (DCs) infiltration was better in responding tumors than in non-responding tumors. Our results of ctDNA revealed a higher positive rate (100%) among patients with HCC with stage IIb-IIIa disease. When comparing patients with pCR/MPR and non-MPR, we observed more mutations in patients who achieved pCR/MPR at baseline (6 mutations vs 2.5 mutations, p=0.025). Patients who were ctDNA positive after adjuvant therapy presented a trend of shorter RFS than those who were ctDNA negative. Proteomic analysis suggested that abnormal glucose metabolism in patients with multifocal HCC might be related to different sensitivity of treatment in different lesions. CONCLUSION:Perioperative camrelizumab plus apatinib displays a promising efficacy and manageable toxicity in patients with resectable HCC. DCs infiltration might be a predictive marker of response to camrelizumab and apatinib as well as patients' recurrence. ctDNA as a compose biomarker can predict pathological response and relapse. Abnormal glucose metabolism in patients with multifocal HCC may be related to different sensitivity of treatment in different lesions. TRIAL REGISTRATION NUMBER:NCT04297202. 10.1136/jitc-2022-004656
    Comprehensive Treatment of Trans-Arterial Chemoembolization Plus Lenvatinib Followed by Camrelizumab for Advanced Hepatocellular Carcinoma Patients. Liu Juanfang,Li Zhen,Zhang Wenguang,Lu Huibin,Sun Zhanguo,Wang Guozheng,Han Xinwei Frontiers in pharmacology This study aimed to report the efficacy and safety of -arterial chemoembolization (TACE) plus lenvatinib and camrelizumab in patients with advanced hepatocellular carcinoma (HCC). This retrospective study enrolled 22 patients with advanced HCC from March 2018 to December 2019. All the patients received comprehensive treatment with TACE plus lenvatinib followed by camrelizumab. Overall survival (OS) and progression-free survival (PFS) were calculated and analysed using the Kaplan-Meier method and log-rank test. Treatment response and adverse events (AEs) were also evaluated. The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 68.2 and 100% at the first month and 72.7 and 95.5% at the third month, respectively. The median OS was 24 months (95% CI, 20.323-27.677 months), and the median PFS was 11.4 months (95% CI, 8.846-13.954 months). The majority of treatment-related adverse reactions were mild or moderate, except for 4 that developed to grade 3-4 (3 reactions of grade 3, 1 reaction of grade 4). No deaths or other serious adverse reactions occurred. -arterial chemoembolization plus lenvatinib and camrelizumab shows good results incontrolling tumour progression and prolonging median OS in patients with advanced HCC. 10.3389/fphar.2021.709060
    Late combination of transarterial chemoembolization with apatinib and camrelizumab for unresectable hepatocellular carcinoma is superior to early combination. Ju Shuguang,Zhou Chen,Hu Junwen,Wang Yingliang,Wang Chaoyang,Liu Jiacheng,Yang Chongtu,Huang Songjiang,Li Tongqiang,Chen Yang,Bai Yaowei,Yao Wei,Xiong Bin BMC cancer OBJECTIVE:The purpose of this study was to explore the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib and camrelizumab (TACE + AC) for unresectable hepatocellular carcinoma (HCC), and the impact of the timing of the combination on it. METHODS:In this single-arm retrospective study, consecutive data of patients with unresectable HCC treated to our hospital from March 2017 to September 2021 were collected. These patients were treated with TACE and started on camrelizumab and apatinib within one week of TACE. Camrelizumab 200 mg intravenously once every three weeks and apatinib 250 mg orally once daily. Repeat TACE treatment was available on an on-demand basis. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. The univariate and multivariate Cox regression analyses were used to assess the effect of early and late combination on OS and PFS. RESULTS:A total of 80 patients were enrolled in this study. The median OS was 22.1 months (95% confidence interval [CI]: 13.8-30.5 months) and the median PFS was 15.7 months (95% CI: 14.7-16.6 months). The ORR was 58.8% (95% CI: 47.2-69.6) and DCR reached 81.2% (95% CI: 71.0-89.1). Multivariable Cox proportional hazard regression analyses showed that TACE late combined with apatinib and camrelizumab provided better OS than early combination (HR = 0.175, 95% CI:0.060-0.509, P = 0.001), as did PFS (HR = 0.422, 95% CI:0.184-0.967, P = 0.041). All treatment-related adverse events were tolerable, and no serious adverse events were observed. CONCLUSION:TACE combined with apatinib plus camrelizumab for patients with unresectable HCC has promising antitumor activity and a manageable safety profile. For unresectable HCC with large tumor burden, late combination provides better OS and PFS compared to early combination. 10.1186/s12885-022-09451-1
    Anti-PD-1 combined sorafenib versus anti-PD-1 alone in the treatment of advanced hepatocellular cell carcinoma: a propensity score-matching study. Chen San-Chi,Huang Yi-Hsiang,Chen Ming-Huang,Hung Yi-Ping,Lee Rheun-Chuan,Shao Yu-Yun,Chao Yee BMC cancer BACKGROUND:Vascular endothelial growth factor (VEGF) plays a role in the tumor microenvironment. Sorafenib, which inhibits the VEGF pathway, has an immune-modulation function but lacks substantial clinical data. This study aims to explore the efficacy of anti-PD-1 combined sorafenib in advanced hepatocellular carcinoma (HCC). METHODS:HCC patients who underwent anti-PD-1 treatment at Taipei Veterans General Hospital (Taipei, Taiwan) between January 2016 and February 2019 were reviewed. The efficacy was compared between groups after propensity-score matching. RESULTS:There were 173 HCC patients receiving anti-PD-1. After excluding unsuitable cases, 140 patients were analyzed, of which 58 received combination therapy and 82 received anti-PD-1 alone. The combination therapy had a trend of higher CR rate (8.6% vs. 4.9%, ns.), ORR (22.4% vs. 19.5%, ns.) and significantly higher DCR (69.0% vs. 37.8%, p < 0.05) comparing to anti-PD-1 alone. After matching, combination group achieved longer progression-free survival (3.87 vs. 2.43 months, p < 0.05) and overall survival (not reached vs. 7.17 months, p < 0.05) than anti-PD-1 alone, without higher grade 3/4 AE (10.3% vs. 7.1%, p = 0.73). The tumor response varied among different metastatic sites, with high responses in adrenal glands, peritoneum and lungs. The more AFP declined (> 10, > 50 and > 66%), the higher the ORR (70, 80 and 92%) and CR rates (30, 35 and 58%) were achieved at day 28. CONCLUSIONS:This is the first study to demonstrate the combination of anti-PD-1 and sorafenib had better efficacy and survival benefit. A prospective randomized study is needed to confirm this finding. 10.1186/s12885-022-09173-4
    Efficacy of Sorafenib Combined With Immunotherapy Following Transarterial Chemoembolization for Advanced Hepatocellular Carcinoma: A Propensity Score Analysis. Frontiers in oncology Aim:The aim of the study is to compare the efficacy and safety of monotherapy with a sequential immune checkpoint inhibitor (ICI) programmed cell death protein-1 (PD-1) and its combination with multi-target drug sorafenib after transcatheter arterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC). Methods:We conducted a retrospective evaluation of patients with advanced HCC who had received sequential PD-1 sorafenib (duplex group, n = 25) or monotherapy PD-1 alone (PD-1 group, n = 41) after TACE during April 2018-September 2021. Propensity score matching (PSM) was applied to correct the selection bias, and 22 pairs were created. The objective response rate (ORR), duration of the overall response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events were analyzed for both groups. Results:After PSM, the median PFS (7.63 vs. 2.9 months; p = 0.0335) was significantly longer for the duplex group than for the PD-1 group. The median OS (21.63 vs. 16.43 months; p = 0.103) was longer for the duplex group than for the PD-1 group, albeit without any statistical difference. The CR rate, ORR, DCR, and PFS rates at the first, third, and sixth months were higher for the duplex group than for the PD-1 group, wherein the PFS rate of the third and sixth months were statistically different. The OS rates at the sixth, 12th, and 18th months were better for the duplex group than for the PD-1 group, while the 18th-month OS rate (54.5% vs. 33.9%, p = 0.030) were statistically different between them. The most common adverse events after TACE included liver function injury, leukocytopenia, and thrombocytopenia, albeit without any statistical differences between the groups. Cox regression analysis showed that sorafenib combined immunotherapy after TACE and the achieving of CR or PR during the treatment were independent factors affecting PFS. Moreover, CNLC stage-IIIa, TACE frequency ≤2, and achievement of CR or PR were independent influencing factors of OS. Conclusions:Sequential PD-1 combined with sorafenib therapy after TACE for advanced HCC treatment is safe and effective, especially for patients with good initial treatment response, to further improve the disease prognosis. 10.3389/fonc.2022.807102
    Combination of Sorafenib, Camrelizumab, Transcatheter Arterial Chemoembolization, and Stereotactic Body Radiation Therapy as a Novel Downstaging Strategy in Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Case Series Study. Frontiers in oncology BACKGROUND AND AIM:Although the treatment effect and availability of therapeutic options for advanced hepatocellular carcinoma (HCC) are limited, the downstaging strategy may improve patient prognosis. This study aimed to investigate the potential of combination therapy as a downstaging strategy for treating advanced HCC with portal vein tumor thrombus (PVTT). METHODS:This retrospective case series included patients having advanced HCC with PVTT, who received the combination therapy of sorafenib, camrelizumab, transcatheter arterial chemoembolization (TACE), and stereotactic body radiation therapy (SBRT) from January 2019 to December 2019 in Xiangya Hospital, Central South University. The downstaging rate, treatment responses, progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities were evaluated. RESULTS:Of the 13 patients, HCC downstaging was achieved in 4 (33.3%) patients who later received hepatectomy. The overall response rate was 41.7%, and the disease control rate was 50.0%. The median PFS time was 15.7 months, with a 1-year PFS rate of 58.3%, whereas the median OS was not reached after 1 year (1-year OS, 83.3%). No severe adverse events or grade 3-4 adverse effect was observed in 12 of the 13 enrolled patients; therapy had to be discontinued in only one patient due to adverse events, who was excluded from the study. The most common adverse effect was fever ( = 4, 33.3%), followed by skin reaction ( = 3, 25%). CONCLUSION:A combination therapy comprising sorafenib, camrelizumab, TACE, and SBRT is an effective downstaging strategy for advanced HCC with PVTT and is associated with few adverse events. 10.3389/fonc.2021.650394
    Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant. Cucchetti Alessandro,Serenari Matteo,Sposito Carlo,Di Sandro Stefano,Mosconi Cristina,Vicentin Ilaria,Garanzini Enrico,Mazzaferro Vincenzo,De Carlis Luciano,Golfieri Rita,Spreafico Carlo,Vanzulli Angelo,Buscemi Vincenzo,Ravaioli Matteo,Ercolani Giorgio,Pinna Antonio Daniele,Cescon Matteo Journal of hepatology BACKGROUND & AIMS:In the context of liver transplantation (LT) for hepatocellular carcinoma (HCC), prediction models are used to ensure that the risk of post-LT recurrence is acceptably low. However, the weighting that 'response to neoadjuvant therapies' should have in such models remains unclear. Herein, we aimed to incorporate radiological response into the Metroticket 2.0 model for post-LT prediction of "HCC-related death", to improve its clinical utility. METHODS:Data from 859 transplanted patients (2000-2015) who received neoadjuvant therapies were included. The last radiological assessment before LT was reviewed according to the modified RECIST criteria. Competing-risk analysis was applied. The added value of including radiological response into the Metroticket 2.0 was explored through category-based net reclassification improvement (NRI) analysis. RESULTS:At last radiological assessment prior to LT, complete response (CR) was diagnosed in 41.3%, partial response/stable disease (PR/SD) in 24.9% and progressive disease (PD) in 33.8% of patients. The 5-year rates of "HCC-related death" were 3.1%, 9.6% and 13.4% in those with CR, PR/SD, or PD, respectively (p <0.001). LogAFP (p <0.001) and the sum of number and diameter of the tumour/s (p <0.05) were determinants of "HCC-related death" for PR/SD and PD patients. To maintain the post-LT 5-year incidence of "HCC-related death" <30%, the Metroticket 2.0 criteria were restricted in some cases of PR/SD and in all cases with PD, correctly reclassifying 9.4% of patients with "HCC-related death", at the expense of 3.5% of patients who did not have the event. The overall/net NRI was 5.8. CONCLUSION:Incorporating the modified RECIST criteria into the Metroticket 2.0 framework can improve its predictive ability. The additional information provided can be used to better judge the suitability of candidates for LT following neoadjuvant therapies. LAY SUMMARY:In the context of liver transplantation for patients with hepatocellular carcinoma, prediction models are used to ensure that the risk of recurrence after transplantation is acceptably low. The Metroticket 2.0 model has been proposed as an accurate predictor of "tumour-related death" after liver transplantation. In the present study, we show that its accuracy can be improved by incorporating information relating to the radiological responses of patients to neoadjuvant therapies. 10.1016/j.jhep.2020.03.018
    Metroticket 2.0 Model for Analysis of Competing Risks of Death After Liver Transplantation for Hepatocellular Carcinoma. Mazzaferro Vincenzo,Sposito Carlo,Zhou Jian,Pinna Antonio D,De Carlis Luciano,Fan Jia,Cescon Matteo,Di Sandro Stefano,Yi-Feng He,Lauterio Andrea,Bongini Marco,Cucchetti Alessandro Gastroenterology BACKGROUND & AIMS:Outcomes of liver transplantation for hepatocellular carcinoma (HCC) are determined by cancer-related and non-related events. Treatments for hepatitis C virus infection have reduced non-cancer events among patients receiving liver transplants, so reducing HCC-related death might be an actionable end point. We performed a competing-risk analysis to evaluate factors associated with survival of patients with HCC and developed a prognostic model based on features of HCC patients before liver transplantation. METHODS:We performed multivariable competing-risk regression analysis to identify factors associated with HCC-specific death of patients who underwent liver transplantation. The training set comprised 1018 patients who underwent liver transplantation for HCC from January 2000 through December 2013 at 3 tertiary centers in Italy. The validation set comprised 341 consecutive patients who underwent liver transplantation for HCC during the same period at the Liver Cancer Institute in Shanghai, China. We collected pretransplantation data on etiology of liver disease, number and size of tumors, patient level of α-fetoprotein (AFP), model for end-stage liver disease score, tumor stage, numbers and types of treatment, response to treatments, tumor grade, microvascular invasion, dates, and causes of death. Death was defined as HCC-specific when related to HCC recurrence after transplantation, disseminated extra- and/or intrahepatic tumor relapse and worsened liver function in presence of tumor spread. The cumulative incidence of death was segregated for hepatitis C virus status. RESULTS:In the competing-risk regression, the sum of tumor number and size and of log level of AFP were significantly associated with HCC-specific death (P < .001), returning an average c-statistic of 0.780 (95% confidence interval, 0.763-0.798). Five-year cumulative incidence of non-HCC-related death was 8.6% in HCV-negative patients and 18.1% in HCV-positive patients. For patients with HCC to have a 70% chance of HCC-specific survival 5 years after transplantation, their level of AFP should be <200 ng/mL and the sum of number and size of tumors (in centimeters) should not exceed 7; if the level of AFP was 200-400 ng/mL, the sum of the number and size of tumors should be ≤5; if their level of AFP was 400-1000 ng/mL, the sum of the number and size of tumors should be ≤4. In the validation set, the model identified patients who survived 5 years after liver transplantation with 0.721 accuracy (95% confidence interval, 0.648%-0.793%). Our model, based on patients' level of AFP and HCC number and size, outperformed the Milan; University of California, San Francisco; Shanghai-Fudan; Up-to-7 criteria (P < .001); and AFP French model (P = .044) to predict which patients will survive for 5 years after liver transplantation. CONCLUSIONS:We developed a model based on level of AFP, tumor size, and tumor number, to determine risk of death from HCC-related factors after liver transplantation. This model might be used to select end points and refine selection criteria for liver transplantation for patients with HCC. To predict 5-year survival and risk of HCC-related death using an online calculator, please see www.hcc-olt-metroticket.org/. ClinicalTrials.gov ID NCT02898415. 10.1053/j.gastro.2017.09.025
    Transarterial chemoembolization (TACE) combined with apatinib versus TACE combined with sorafenib in advanced hepatocellular carcinoma patients: a multicenter retrospective study. Qiu Zhiyu,Shen Lujun,Jiang Yiquan,Qiu Jiliang,Xu Zining,Shi Mengting,Yu Zhentao,Ma Yanping,He Wei,Zheng Yun,Li Binkui,Wang Guoying,Yuan Yunfei Annals of translational medicine Background:The combination of transarterial chemoembolization (TACE) with sorafenib has demonstrated superior efficacy over sorafenib and TACE monotherapy in hepatocellular carcinoma (HCC). Apatinib, a new targeted agent, has been recently reported to prolong the survival of HCC patients, either alone or in combination with TACE. However, the superior regimen between TACE-apatinib and TACE-sorafenib in HCC patients has not been determined. In this study, we compared the efficacy and safety of TACE-apatinib versus TACE-sorafenib in advanced stage HCC patients. Methods:The data of 201 HCC patients who had received TACE-sorafenib or TACE-apatinib between January 2016 and June 2018 in three hospitals were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and adverse effects (AEs) between the two treatment groups were compared. A subgroup analysis based on the doses of targeted agents was also performed. Results:No significant differences in baseline clinicopathological features were found between the two groups except for dose reduction. The TACE-apatinib group had higher incidences of hypertension, oral or anal ulcer and proteinuria, while the TACE-sorafenib group had higher incidences of diarrhea and alopecia. Grade 3/4 AEs occurred more frequently in the TACE-apatinib group than in the TACE-sorafenib group (52.3% 22.6%, P<0.001). The TACE-sorafenib group had better PFS than the TACE-apatinib group (median PFS: 5.0 6.0 months, P=0.002) while the two groups showed no difference in OS (median OS: 13.0 13.0 months, P=0.448). The TACE-apatinib group had a higher rate of targeted agent dose reduction than the TACE-sorafenib group (53.5% 17.4%, P<0.001). When the patients were stratified into normal and reduced-dose subgroups, those who received TACE-sorafenib exhibited improved PFS but similar OS compared with the patients who received TACE-apatinib in the reduced-dose subgroup (median OS: 12.0 13.3 months, P=0.614; median PFS: 3.0 7.0 months, P<0.001). Multivariable analysis validated that treatments and dose reduction were independent prognostic factors for PFS among all patients. Conclusions:Compared with TACE-sorafenib, the strategy of TACE-apatinib yielded shorter PFS in advanced HCC patients while no difference in OS was observed. A high rate of AE-related dose reduction of apatinib could account for the observed differences. 10.21037/atm-20-5360
    Apatinib Plus Camrelizumab With/Without Chemoembolization for Hepatocellular Carcinoma: A Real-World Experience of a Single Center. Frontiers in oncology OBJECTIVE:This study was conducted in order to compare the efficacy and safety of transarterial chemoembolization (TACE) plus apatinib plus camrelizumab (TACE+AC) and apatinib plus camrelizumab (AC) in the treatment of unresectable hepatocellular carcinoma (HCC) in a real-world setting. METHODS:In this single-center retrospective study, the data of patients with unresectable HCC who had received TACE+AC or AC treatment during March 2017 to May 2021 were assessed. Patients in the AC group received intravenous administration of camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg/day treatment. Patients in the TACE+AC group received the same dose of camrelizumab and apatinib 1 week after TACE. The primary endpoint of the study was overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) as the secondary endpoints. RESULTS:A total of 108 patients were enrolled in the study. There were 52 patients in the AC group and 56 patients in TACE+AC group. Median OS was significantly longer in the TACE+AC group than in the AC group (24.8 vs. 13.1 months; = 0.005). Patients in the TACE+AC group achieved a higher ORR [24 (42.9%) vs. 9 (17.3%), = 0.004] than those in the AC group. Patients in the TACE+AC group also achieved a higher disease control rate (DCR) [48 (85.7%) vs. 30 (57.7%), = 0.001] than patients in the AC group. There was no significant difference in the incidence of AEs related to apatinib and camrelizumab between the two groups, except for gastrointestinal reaction ( > 0.05, all; < 0.05, gastrointestinal reaction). CONCLUSION:TACE plus apatinib plus camrelizumab significantly improved OS, ORR, and DCR over apatinib plus camrelizumab in patients with unresectable HCC. AEs were tolerable and manageable. 10.3389/fonc.2021.835889
    Lenvatinib Plus Camrelizumab versus Lenvatinib Monotherapy as Post-Progression Treatment for Advanced Hepatocellular Carcinoma: A Short-Term Prognostic Study. Cancer management and research OBJECTIVE:Compared the outcomes between lenvatinib plus camrelizumab therapy and lenvatinib monotherapy as post-progression treatment for advanced hepatocellular carcinoma (HCC) with progressive disease (PD). PATIENTS AND METHODS:A total of 48 advanced HCC patients were included in this retrospective study between June 2019 and March 2020. The patients were divided into the lenvatinib plus camrelizumab group (n=21) and the lenvatinib group (n=27). Primary endpoints were overall survival (OS) and progression-free survival (PFS), and secondary endpoints were the objective response rate (ORR) and adverse events (AEs). RESULTS:The median follow-up time was 8.4 months. The median OS was not obtained. The median PFS of lenvatinib plus camrelizumab group was significantly longer than that of lenvatinib group (8.0 months vs 4.0 months, =0.011). Compared with lenvatinib group, lenvatinib plus camrelizumab group had higher ORR (28.57% vs 7.41%) and disease control rate (DCR) (71.43% vs 51.85%). The most common adverse events (AEs) included hand-foot skin reaction, hypertensions and abnormal hepatic function damage. Overall, 23.81% and 25.93% of patients experienced grade ≥3AEs in the lenvatinib plus camrelizumab group and the lenvatinib group, respectively. CONCLUSION:Lenvatinib plus camrelizumab as post-progression treatment is effective and safe for advanced hepatocellular carcinoma with PD. 10.2147/CMAR.S304820
    Single-cell immune signature for detecting early-stage HCC and early assessing anti-PD-1 immunotherapy efficacy. Shi Jiawei,Liu Junwei,Tu Xiaoxuan,Li Bin,Tong Zhou,Wang Tian,Zheng Yi,Shi Hongyu,Zeng Xun,Chen Wei,Yin Weiwei,Fang Weijia Journal for immunotherapy of cancer BACKGROUND:The early diagnosis of hepatocellular carcinoma (HCC) can greatly improve patients' 5-year survival rate, and the early efficacy assessment is important for oncologists to harness the anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced HCC. The lack of effective predicting biomarkers not only leads to delayed detection of the disease but also results in ineffective immunotherapy and limited clinical survival benefit. METHODS:We exploited the single-cell approach (cytometry by time of flight (CyTOF)) to analyze peripheral blood mononuclear cells from multicohorts of human samples. Immune signatures for different stages of patients with HCC were systematically profiled and statistically compared. Furthermore, the dynamic changes of peripheral immune compositions for both first-line and second-line patients with HCC after anti-PD-1 monotherapy were also evaluated and systematically compared. RESULTS:We identified stage-specific immune signatures for HCC and constructed a logistic AdaBoost-SVM classifier based on these signatures. The classifier provided superior performance in predicting early-stage HCC over the commonly used serum alpha-fetoprotein level. We also revealed the treatment stage-specific immune signatures from peripheral blood and their dynamical changing patterns, all of which were integrated to achieve early discrimination of patients with non-durable benefit for both first-line and second-line anti-PD-1 monotherapies. CONCLUSIONS:Our newly identified single-cell peripheral immune signatures provide promising non-invasive biomarkers for early detection of HCC and early assessment for anti-PD-1 immunotherapy efficacy in patients with advanced HCC. These new findings can potentially facilitate early diagnosis and novel immunotherapy for patients with HCC in future practice and further guide the utility of CyTOF in clinical translation of cancer research. TRIAL REGISTRATION NUMBERS:NCT02576509 and NCT02989922. 10.1136/jitc-2021-003133
    Camrelizumab Plus Sorafenib Sorafenib Monotherapy for Advanced Hepatocellular Carcinoma: A Retrospective Analysis. Frontiers in oncology BACKGROUND:Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis. Immunotherapy has gained great interest for various solid tumors due to its promising clinical efficacy. Targeted therapy also plays a crucial role in anticancer treatment. However, studies on the combination of immunotherapy and targeted therapy for advanced HCC are limited. Thus, the objective of this study was to investigate the efficacy and safety of camrelizumab combined with sorafenib in the treatment of advanced HCC. METHODS:From January 2019 to January 2021, 100 consecutive patients with advanced HCC in our hospital were enrolled for this study. Patients were assigned into two groups: a combined-therapy group (camrelizumab + sorafenib) and a sorafenib-only group. Progression-free survival (PFS), overall survival (OS), treatment response, and relevant adverse effects (AEs) were evaluated and recorded. RESULTS:Of a total of 100 patients, 35 received a combination of camrelizumab and sorafenib, and 65 were treated with sorafenib alone. After 1:1 propensity score matching (PSM), each group had 34 patients. The overall response rate (ORR) of the combined-therapy group was statistically significantly higher than that of the sorafenib-only group (before PSM, = 0.037; after PSM, = 0.010). However, there was no significant difference in disease control rate (DCR) between the two groups (before PSM, = 0.695; after PSM, = 1.000). Patients who received the combination therapy had significantly longer PFS than those who received the sorafenib monotherapy (before PSM, = 0.041; after PSM, = 0.043). However, the two groups exhibited comparable median OS (before PSM, = 0.135; after PSM, = 0.105). Although the combined-therapy group showed a higher incidence of AEs such as thrombocytopenia than the sorafenib-only group after PSM, most of these AEs were easily controlled after treatment. CONCLUSION:Camrelizumab plus sorafenib showed favorable efficacy and manageable toxicity for patients with advanced HCC. However, more prospective randomized trials are necessary to further verify the potential clinical benefits of this combination therapy. 10.3389/fonc.2021.694409